Substituted Diazabicycloalkane Derivates

ABSTRACT

Compounds of formula (I) 
       Z-Ar 1 —Ar 2    (I)
 
     wherein Z is a diazabicyclic amine, Ar 1  is a 5- or 6-membered aromatic ring, and Ar 2  is selected from the group consisting of an unsubstituted or substituted 5- or 6-membered heteroaryl ring; unsubstituted or substituted bicyclic heteroaryl ring; 3,4-(methylenedioxy)phenyl; carbazolyl; tetrahydrocarbazolyl; naphthyl; and phenyl; wherein the phenyl is substituted with 0, 1, 2, or 3 substituents in the meta- or para-positions. The compounds are useful in treating conditions or disorders prevented by or ameliorated by α7 nAChR ligands. Also disclosed are pharmaceutical compositions comprising compounds of formula (I) and methods for using such compounds and compositions.

This application is a divisional application of U.S. non-Provisionalapplication Ser. No. 10/942,035, filed Sep. 16, 2004, which claimspriority to U.S. Provisional Application Ser. No. 60/504,353, filed Sep.19, 2003, which are hereby incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Technical Field

The invention relates to diazabicycloalkane derivatives, compositionscomprising such compounds, and methods of treating conditions anddisorders using such compounds and compositions.

2. Description of Related Technology

Nicotinic acetylcholine receptors (nAChRs) are widely distributedthroughout the central (CNS) and peripheral (PNS) nervous systems. Suchreceptors play an important role in regulating CNS function,particularly by modulating release of a wide range of neurotransmitters,including, but not necessarily limited to acetylcholine, norepinephrine,dopamine, serotonin and GABA. Consequently, nicotinic receptors mediatea very wide range of physiological effects, and have been targeted fortherapeutic treatment of disorders relating to cognitive function,learning and memory, neurodegeneration, pain and inflammation, psychosisand sensory gating, mood and emotion, among others.

Many subtypes of the nAChR exist in the CNS and periphery. Each subtypehas a different effect on regulating the overall physiological function.Typically, nAChRs are ion channels that are constructed from apentameric assembly of subunit proteins. At least 12 subunit proteins,α2-α10 and β2-β4, have been identified in neuronal tissue. Thesesubunits provide for a great variety of homomeric and heteromericcombinations that account for the diverse receptor subtypes. Forexample, the predominant receptor that is responsible for high affinitybinding of nicotine in brain tissue has composition (α4)₂(β2)₃ (the α4β2subtype), while another major population of receptors is comprised ofthe homomeric (α7)₅ (the α7 subtype).

Certain compounds, like the plant alkaloid nicotine, interact with allsubtypes of the nAChRs, accounting for the profound physiologicaleffects of this compound. While nicotine has been demonstrated to havemany beneficial properties, not all of the effects mediated by nicotineare desirable. For example, nicotine exerts gastrointestinal andcardiovascular side effects that interfere at therapeutic doses, and itsaddictive nature and acute toxicity are well-known. Ligands that areselective for interaction with only certain subtypes of the nAChR offerpotential for achieving beneficial therapeutic effects with an improvedmargin for safety.

The α7 nAChRs have been shown to play a significant role in enhancingcognitive function, including aspects of learning, memory and attention(Levin, E. D., J. Neurobiol. 53: 633-640, 2002). For example, α7 nAChRshave been linked to conditions and disorders related to attentiondeficit disorder, attention deficit hyperactivity disorder (ADHD),Alzheimer's disease (AD), mild cognitive impairment, senile dementia,dementia associated with Lewy bodies, dementia associated with Down'ssyndrome, AIDS dementia, Pick's Disease, as well as cognitive deficitsassociated with schizophrenia, among other systemic activities.

The activity at the α7 nAChRs can be modified or regulated by theadministration of α7 nAChR ligands. The ligands can exhibit antagonist,agonist, partial agonist, or inverse agonist properties. Thus, α7ligands have potential in treatment of various cognitive disorders.

Although various classes of compounds demonstrating α7 nAChR-modulatingactivity exist, it would be beneficial to provide additional compoundsdemonstrating activity at the α7 nAChRs that can be incorporated intopharmaceutical compositions useful for therapeutic methods.Specifically, it would be beneficial to provide compounds that interactselectively with α7-containing neuronal nAChRs compared to othersubtypes.

SUMMARY OF THE INVENTION

The invention is directed to diazabicycloalkane derivative compounds aswell as compositions comprising such compounds, and method of using thesame. Compounds of the invention have the formula:

Z-Ar₁—Ar₂  (I)

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof,wherein:

Z is a diazabicyclic amine of the formula:

Ar₁ is a 5- or 6-membered aromatic ring of the formula (a) or (b):

Ar₂ is selected from the group consisting of an unsubstituted orsubstituted 5- or 6-membered heteroaryl ring; unsubstituted orsubstituted bicyclic heteroaryl ring; 3,4-(methylenedioxy)phenyl;carbazolyl; tetrahydrocarbazolyl; naphthyl; and phenyl; wherein thecarbazolyl; tetrahydrocarbazolyl; naphthyl; and phenyl is substitutedwith 0, 1, 2, or 3 substituents selected from the group consisting ofalkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxysulfonyl, alkyl, alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy,alkylsulfonyl, alkylthio, alkynyl, carboxy, cyano, formyl, haloalkoxy,haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro,—NR_(A)R_(B), (NR_(A)R_(B))alkyl, (NR_(A)R_(B))carbonyl,(NR_(A)R_(B))sulfonyl, and phenyl; provided that when Y₁ is O or S, Y₂is N, Y₃ is —CR₃ and R₃ is hydrogen, and Y₄ is C, then Ar₂ is not5-tetrazolyl;

X₁, X₂, X₃, and X₄ are each independently selected from the groupconsisting of N and —CR₃, provided that R₃ is not hydrogen at least inone occurrence when X₁, X₂, X₃, and X₄ are all —CR₃;

Y₁, Y₂, and Y₃ are each independently selected from the group consistingof N, O, S, and —CR₃;

Y₄ is selected from the group consisting of C and N, provided that whenY₄ is C at least one of Y₁, Y₂, and Y₃, is other than —CR₃;

l, m, n, o, and p are each independently selected from the groupconsisting of 0, 1, or 2, provided that the sum total of l, m, n, o, andp is 3, 4, or 5, and further provided that the sum of l and o is atleast 1 and the sum of m and p is at least 1;

R₁ is selected from the group consisting of hydrogen, alkenyl, alkylalkoxycarbonyl, arylalkyl, and heteroarylalkyl;

R₂ at each occurrence is independently selected from the groupconsisting of hydrogen, alkoxycarbonyl, and alkyl;

R₃ at each occurrence is independently selected from the groupconsisting of hydrogen and alkyl;

R_(A) and R_(B) are each independently selected from the groupconsisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl,arylcarbonyl, formyl and (NR_(C)R_(D))sulfonyl; and

R_(C) and R_(D) are each independently selected from the groupconsisting of hydrogen and alkyl.

Another aspect of the invention relates to pharmaceutical compositionscomprising compounds of the invention. Such compositions can beadministered in accordance with a method of the invention, typically aspart of a therapeutic regimen for treatment or prevention of conditionsand disorders related to nAChR activity, and more particularly α7 nAChRactivity.

Yet another aspect of the invention relates to a method of selectivelymodulating to nAChR activity, for example α7 nAChR activity. The methodis useful for treating and/or preventing conditions and disordersrelated to α7 nAChR activity modulation in mammals. More particularly,the method is useful for conditions and disorders related to attentiondeficit disorder, attention deficit hyperactivity disorder (ADHD),Alzheimer's disease (AD), mild cognitive impairment, senile dementia,AIDS dementia, Parkinson's disease, Pick's Disease, dementia associatedwith Lewy bodies, dementia associated with Down's syndrome, amyotrophiclateral sclerosis, Huntington's disease, diminished CNS functionassociated with traumatic brain injury, acute pain, post-surgical pain,chronic pain, inflammatory pain, neuropathic pain, infertility, need fornew blood vessel growth associated with wound healing, need for newblood vessel growth associated with vascularization of skin grafts, andlack of circulation, more particularly circulation around a vascularocclusion, among other systemic activities.

The compounds, compositions comprising the compounds, and methods fortreating or preventing conditions and disorders by administering thecompounds are further described herein.

DETAILED DESCRIPTION OF THE INVENTION Definition of Terms

Certain terms as used in the specification are intended to refer to thefollowing definitions, as detailed below.

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy” means an alkyl group, as defined herein, appended tothe parent molecular moiety through an oxygen atom. Representativeexamples of alkoxy include, but are not limited to, methoxy, ethoxy,propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

The term “alkoxyalkoxy” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through anotheralkoxy group, as defined herein. Representative examples of alkoxyalkoxyinclude, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy,2-methoxyethoxy, and methoxymethoxy.

The term “alkoxyalkyl” as used herein, means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of alkoxyalkyl include, butare not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl,and methoxymethyl.

The term “alkoxycarbonyl” means an alkoxy group, as defined herein,appended to the parent molecular moiety through a carbonyl group,represented by —C(O)—, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxysulfonyl” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkoxysulfonyl include, but are not limited to, methoxysulfonyl,ethoxysulfonyl and propoxysulfonyl.

The term “alkyl” means a straight or branched chain hydrocarboncontaining from 1 to 6 carbon atoms. Representative examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, and n-hexyl.

The term “alkylcarbonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “alkylcarbonyloxy” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an oxygen atom. Representative examples of alkylcarbonyloxyinclude, but are not limited to, acetyloxy, ethylcarbonyloxy, andtert-butylcarbonyloxy.

The term “alkylsulfonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkylsulfonyl include, but are not limited to, methylsulfonyl andethylsulfonyl.

The term “alkylthio” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of alkylthio include, but are not limited,methylthio, ethylthio, tert-butylthio, and hexylthio.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “aromatic” refers to a planar or polycyclic structurecharacterized by a cyclically conjugated molecular moiety containing4n+2 electrons, wherein n is the absolute value of an integer. Aromaticmolecules containing fused, or joined, rings also are referred to asbicylic aromatic rings. For example, bicyclic aromatic rings containingheteroatoms in a hydrocarbon ring structure are referred to as bicyclicheteroaryl rings.

The term “aryl,” as used herein, means a phenyl group or a naphthylgroup.

The aryl groups of the present invention can be optionally substitutedwith one, two, three, four, or five substituents independently selectedfrom the group consisting of alkenyl, alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy,alkylthio, alkynyl, carboxy, cyano, haloalkoxy, haloalkyl, halogen,hydroxy, hydroxyalkyl, mercapto, and nitro.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of arylalkyl include, but arenot limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and2-naphth-2-ylethyl.

The term “arylcarbonyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through a carbonylgroup, as defined herein. Representative examples of arylcarbonylinclude, but are not limited to, benzoyl and naphthoyl.

The term “carbonyl” as used herein, means a —C(O)— group.

The term “carboxy” as used herein, means a —CO₂H group.

The term “cyano” as used herein, means a —CN group.

The term “formyl” as used herein, means a —C(O)H group.

The term “halo” or “halogen” means —Cl, —Br, —I or —F.

The term “haloalkoxy” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of haloalkoxyinclude, but are not limited to, chloromethoxy, 2-fluoroethoxy,trifluoromethoxy, and pentafluoroethoxy.

The term “haloalkyl” means at least one halogen, as defined herein,appended to the parent molecular moiety through an alkyl group, asdefined herein. Representative examples of haloalkyl include, but arenot limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “heteroaryl” means an aromatic five- or six-membered ringcontaining 1, 2, 3, or 4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. The heteroaryl groups are connected to theparent molecular moiety through a carbon or nitrogen atom.Representative examples of heteroaryl include, but are not limited to,furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl,tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, and triazolyl.

The heteroaryl groups of the invention are substituted with 0, 1, 2, or3 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl,alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl,carboxy, cyano, formyl, haloalkoxy, haloalkyl, halo, hydroxy,hydroxyalkyl, mercapto, nitro, —NR_(A)R_(B), (NR_(A)R_(B))carbonyl, and(NR_(A)R_(B))sulfonyl.

The term “bicyclic heteroaryl” refers to fused aromatic nine- andten-membered bicyclic rings containing 1, 2, 3, or 4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. The bicyclicheteroaryl groups are connected to the parent molecular moiety through acarbon or nitrogen atom. Representative examples of bicyclic heteroarylrings include, but are not limited to, indolyl, benzothiazolyl,benzofuranyl, isoquinolinyl, and quinolinyl. Bicyclic heteroaryl groupsof the invention are substituted with 0, 1, 2, or 3 substituentsindependently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy,alkylsulfonyl, alkylthio, alkynyl, carboxy, cyano, formyl, haloalkoxy,haloalkyl, halo, hydroxy, hydroxyalkyl, mercapto, nitro, —NR_(A)R_(B),(NR_(A)R_(B))carbonyl, and (NR_(A)R_(B))sulfonyl.

The term “heteroarylalkyl” as used herein, means a heteroaryl, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of heteroarylalkylinclude, but are not limited to, pyridin-3-ylmethyl and2-(thien-2-yl)ethyl.

The term “hydroxy” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein, means at least one hydroxygroup, as defined herein, is appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “mercapto” as used herein, means a —SH group.

The term “nitro” as used herein, means a —NO₂ group.

The term “—NR_(A)R_(B)” as used herein, means two groups, R_(A) andR_(B), which are appended to the parent molecular moiety through anitrogen atom. R_(A) and R_(B) are each independently hydrogen, alkyl,alkylcarbonyl, alkylsulfonyl, arylcarbonyl, formyl or(NR_(C)R_(D))sulfonyl. Representative examples of —NR_(A)R_(B) include,but are not limited to, amino, methylamino, acetylamino, andacetylmethylamino.

The term “(NR_(A)R_(B))alkyl” as used herein, means a —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples of(NR_(A)R_(B))alkyl include, but are not limited to, (amino)methyl,(dimethylamino)methyl, and (ethylamino)methyl.

The term “(NR_(A)R_(B))alkoxy” as used herein, means a —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough an alkoxy group, as defined herein. Representative examples of(NR_(A)R_(B))alkoxy include, but are not limited to, (amino)methoxy,(dimethylamino)methoxy, and (diethylamino)ethoxy.

The term “(NR_(A)R_(B))carbonyl” as used herein, means a —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(NR_(A)R_(B))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

The term “(NR_(A)R_(B))sulfonyl” as used herein, means a —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples of(NR_(A)R_(B))sulfonyl include, but are not limited to, aminosulfonyl,(methylamino)sulfonyl, (dimethylamino)sulfonyl, and(ethylmethylamino)sulfonyl.

The term “—NR_(C)R_(D)” as used herein, means two groups, R_(C) andR_(D), which are appended to the parent molecular moiety through anitrogen atom. R_(C) and R_(D) are each independently hydrogen or alkyl.Representative examples of —NR_(C)R_(D) include, but are not limited to,amino, methylamino and dimethylamino.

The term “(NR_(C)R_(D))sulfonyl” as used herein, means a —NR_(C)R_(D)group, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples of(NR_(C)R_(D))sulfonyl include, but are not limited to, aminosulfonyl,(methylamino)sulfonyl, (dimethylamino)sulfonyl, and(ethylmethylamino)sulfonyl.

Although typically it may be recognized that an asterisk is used toindicate that the exact subunit composition of a receptor is uncertain,for example α3b4* indicates a receptor that contains the α3 and β4proteins in combination with other subunits, the term α7 as used hereinis intended to include receptors wherein the exact subunit compositionis both certain and uncertain. For example, as used herein α7 includeshomomeric (α7)₅ receptors and α7* receptors, which denote a nAChRcontaining at least one α7 subunit.

Compounds of the Invention

Compounds of the invention can have the formula (I) as described above.More particularly, compounds of formula (I):

Z-Ar₁—Ar₂  (I)

are those wherein Z is a moiety of the formula (II):

wherein R₁, R₂, Ar₁, Ar₂, l, m, n, o, and p are as previously defined.The variables l, m, n, o, and p denote numbers that are eachindependently selected from 0, 1, or 2, provided that the sum total ofl, m, n, o, and p is 3, 4, or 5, such that the group represented by Z isa 7-, 8-, or 9-membered diazabicycloalkane, respectively. Preferably, Zis a 7- or 8-membered ring. In one particular embodiment, n is zero,such that Z is a fused bicyclic ring.

Z can have substituents represented by R₁ and R₂. Examples of moietiessuitable for Z can include, but are not limited to:

The substituent represented by R₁ can be selected from hydrogen,alkoxycarbonyl, alkyl, arylalkyl, and heteroarylalkyl, particularlymethyl, benzyl and pyridin-3-ylmethyl. R₂ can be selected from hydrogen,alkenyl, alkyl, and alkoxycarbonyl, particularly methyl.

The Ar₁ moiety can be selected independently of the moiety selected forZ. Suitable moieties for Ar₁ are those represented by a 5- or 6-memberedaromatic ring of the formula:

In such moieties, X₁, X₂, X₃, and X₄ are each independently selectedfrom the group consisting of N and —CR₃, provided that R₃ is nothydrogen at least in one occurrence when X₁, X₂, X₃, and X₄ all are—CR₃, such that a phenyl group contains at least one substituent. Themoiety represented by formula (a) is attached to the diazabicyclic amineand the Ar₂ moiety by 1,4-substitution or para-attachment. Preferably,the moiety represented by formula (a) contains at least one heteroatom,particularly when Ar₂ is a phenyl group.

Formula (b) represents a five-membered ring wherein Y₁, Y₂, and Y₃ areeach independently selected from the group consisting of N, O, S, and—CR₃.

Y₄ is selected from C or N. When Y₄ is C at least one of thesubstituents represented by Y₁, Y₂, and Y₃, is other than —CR₃, suchthat the moiety represented by formula (b) contains at least oneheteroatom. The moiety generally is attached to the diazabicyclic amineand the Ar₂ moiety by 1,3-substitution.

Examples of specific rings suitable for Ar₁ include, but are not limitedto, isoxazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidinyl, thiadiazolyl, isothiazolyl, thiazolyl, thienyl, and phenyl,wherein the pyridazinyl, pyridyl, and phenyl, are substituted with 0 or1 substitutent selected from the group consisting of alkoxy, alkyl,cyano, and hydroxy. More particularly, the rings represented by Ar₁ are,for example,

The preferred ring for Ar₁ is pyridazinyl, exemplified by (i), whereinR₃ is hydrogen, alkoxy, alkyl, cyano, or hydroxy, wherein hydrogen ormethyl are preferred. Another preferred ring for Ar₁ is pyridyl,exemplified by (ii), wherein R₃ is hydrogen, alkoxy, alkyl, cyano, orhydroxy, wherein hydrogen or cyano are preferred. Another preferred ringfor Ar₁ is pyrimidinyl, exemplified by (iii). Another preferred ring forAr₁ is thiadiazolyl, exemplified by (iv) and (v). Another preferred ringfor Ar₁ is oxadiazolyl, exemplified by (vi). Another preferred ring forAr₁ is pyrazolyl, exemplified by (vii) and (viii). Another preferredring for Ar₁ is isoxazolyl, exemplified by (ix). Another preferred ringfor Ar₁ is thiazolyl, exemplified by (x) and (xi). Another preferredring for Ar₁ is thienyl, exemplified by (xii). Another preferred ringfor Ar₁ is oxazolyl, exemplified by (xiii). Another preferred ring forAr₁ is phenyl, exemplified by (xiv), wherein R₃ is hydrogen, alkoxy,alkyl, cyano, or hydroxy. It is to be understood that either end of therings (i), (ii), (iii), (v), (vii), (ix), (x), (xi), (xii), and (xiii)can be attached to Z.

Ar₂ can be independently selected regardless of the moiety selected forZ or Ar₁. When Ar₂ is phenyl or substituted phenyl, Ar₁ preferablycontains at least one heteroatom. Moieties suitable for Ar₂ can be anunsubstituted or substituted 5- or 6-membered heteroaryl ring; anunsubstituted or substituted bicyclic heteroaryl ring;3,4-(methylenedioxy)phenyl; carbazolyl; tetrahydrocarbazolyl; naphthyl;or phenyl. The carbazolyl, tetrahydrocarbazolyl, naphthyl, and phenylmoieties can be substituted with 0, 1, 2, or 3 substituents preferablyin the meta- or para-position.

Examples of heteroaryl or bicyclic heteroaryl rings are, for example,furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl,tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl,indolyl, benzothiazolyl, benzofuranyl, isoquinolinyl, and quinolinyl.Suitable substituents for the heteroaryl and bicyclic heteroaryl ringinclude, but are not limited to, alkenyl, alkoxy, alkoxyalkoxy,alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl,alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl, carboxy, cyano,formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto,nitro, —NR_(A)R_(B), wherein R_(A) and R_(B) are each independentlyselected from hydrogen, alkyl, alkylcarbonyl, or formyl,(NR_(A)R_(B))carbonyl, and (NR_(A)R_(B))sulfonyl. More particularly, Ar₂are preferably selected from benzofuranyl; benzothienyl; furyl;imidazolyl; 3-methylindazolyl; 3-indolyl; 5-indolyl; 1-methyl-3-indolyl;1-methyl-5-indolyl; 3-methyl-5-indolyl;3-[(dimethylamino)methyl]indolyl; 1-[(4-methylphenyl)sulfonyl]indolyl;3,5-dimethyl isoxazolyl; naphthyl; pyrazolyl; 3,5-dimethylpyrazolyl;1-methylpyrazolyl; 6-oxopyridazinyl; pyridyl; 6-aminopyridyl;2-cyanopyridyl; pyrimidinyl; 2-methoxypyrimidinyl; 2-pyrrolyl;3-pyrrolyl; quinolinyl; or thienyl.

Phenyl and substituted phenyl groups, for example benzodioxolyl and3,4-(methylenedioxy)phenyl, also are suitable for Ar₂. Additionalsuitable substituents for the phenyl ring can include, but are notlimited to, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl,alkylthio, alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl,halogen, hydroxy, hydroxyalkyl, mercapto, nitro, —NR_(A)R_(B),(NR_(A)R_(B))alkyl, (NR_(A)R_(B))carbonyl, (NR_(A)R_(B))sulfonyl, andphenyl. R_(A) and R_(B) are each independently hydrogen, alkyl,alkylcarbonyl, alkylsulfonyl, arylcarbonyl, formyl or(NR_(C)R_(D))sulfonyl. R_(C) and R_(D) are each independently hydrogenor alkyl. For example, Ar₂ can be phenyl substituted with 0, 1, or 2substituents, such as alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl,carboxy, cyano, halogen, haloalkoxy, haloalkyl, hydroxy, nitro,—NR_(A)R_(B), (NR_(A)R_(B))alkyl, (NR_(A)R_(B))alkoxy, and phenyl. Morespecific examples of moieties suitable for Ar₂ include, but are notlimited to:

wherein R₄ at each occurrence is independently selected and represents asubstituent selected from the group consisting of hydrogen, alkoxy,alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halogen,haloalkoxy, haloalkyl, hydroxy, nitro, —NR_(A)R_(B), (NR_(A)R_(B))alkyl,(NR_(A)R_(B))alkoxy, and phenyl. Preferably, the substituent representedby R₄ is selected from the group consisting of hydrogen, alkoxy,alkoxycarbonyl, alkyl, alkylcarbonyl, —NR_(A)R_(B), and haloalkyl.Preferred moieties for Ar₂, particularly when Ar₁ is heteroaryl, arephenyl, para-acetylaminophenyl, meta-aminophenyl, para-aminophenyl,para(2-(diethylamino)ethoxy)phenyl, meta(2-(diethylamino)ethoxy)phenyl,para-(dimethylamino)phenyl, para-bromophenyl, meta-cyanophenyl,para-cyanophenyl, meta-hydroxyphenyl, para-hydroxyphenyl,para-iodophenyl, meta-methylphenyl, para-methylphenyl,3,5-dimethylphenyl, meta-methoxyphenyl, para-methoxyphenyl,meta-trifluoromethoxyphenyl, meta-nitrophenyl, para-nitrophenyl,meta-trifluoromethylphenyl, and the like. When ring of formula (b) isdefined by Y₁ is O or S, Y₂ is N, Y₃ is —CR₃ and R₃ is hydrogen, and Y₄is C, then Ar₂ is not 5-tetrazolyl.

One example of a particular embodiment of the compounds for theinvention is wherein Z is a seven-membered fused bicyclic ring, forexample

Ar₁ is selected from the group consisting of isoxazolyl, oxadiazolyl,oxazolyl, pyrazolyl, pyridazinyl, 4-methylpyridazinyl,5-methylpyridazinyl, pyridyl, 5-cyanopyridyl, pyrimidinyl, thiadiazolyl,thiazolyl, thienyl, and phenyl substituted with 0 or 1 substituentselected from the group consisting alkoxy, alkyl, cyano, and hydroxy;Ar₂ is selected from the group consisting of benzofuranyl, benzothienyl,carbazolyl, tetrahydrocarbazolyl, furyl; imidazolyl, 3-methylindazolyl,3-indolyl, 5-indolyl, 1-methyl-3-indolyl, 1-methyl-5-indolyl,3-methyl-5-indolyl, 3-[(dimethylamino)methyl]indolyl,1-[(4-methylphenyl)sulfonyl]indolyl, 3,5-dimethylisoxazolyl, naphthyl,pyrazolyl, 3,5-dimethylpyrazolyl, 1-methylpyrazolyl, 6-oxopyridazinyl,pyridyl, 6-aminopyridyl, 2-cyanopyridyl, pyrimidinyl,2-methoxypyrimidinyl, 2-pyrrolyl, 3-pyrrolyl, quinolinyl, thienyl,3,4-(methylenedioxy)phenyl, and phenyl, wherein the phenyl issubstituted with 0, 1, or 2 substituents selected from the groupconsisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy,cyano, halogen, haloalkoxy, haloalkyl, hydroxy, nitro, —NR_(A)R_(B),(NR_(A)R_(B))alkyl, (NR_(A)R_(B))alkoxy, and phenyl.

Another example of a particular embodiment of the compounds for theinvention is wherein Z is a seven-membered fused bicyclic ring, forexample

Ar₁ is pyridazinyl or pyridyl, and Ar₂ is as described, either generallyor particularly, and more particularly Ar₂ is selected from the groupconsisting of 3-indolyl, 5-indolyl, 1-methyl-3-indolyl,1-methyl-5-indolyl, 3-methyl-5-indolyl, 3,4-(methylenedioxy)phenyl, andphenyl, wherein the phenyl is substituted with 0, 1, or 2 substituentsselected from the group consisting of alkoxy, alkoxycarbonyl, alkyl,alkylcarbonyl, carboxy, cyano, halogen, haloalkoxy, haloalkyl, hydroxy,nitro, —NR_(A)R_(B), (NR_(A)R_(B))alkyl, (NR_(A)R_(B))alkoxy, andphenyl.

One example of a particular embodiment of the compounds for theinvention is wherein Z is an eight-membered bridged bicyclic ring, forexample

Ar₁ is selected from the group consisting of isoxazolyl, oxadiazolyl,oxazolyl, pyrazolyl, pyridazinyl, 4-methylpyridazinyl,5-methylpyridazinyl, pyridyl, 5-cyanopyridyl, pyrimidinyl, thiadiazolyl,thiazolyl, thienyl, and phenyl substituted with 0 or 1 substituentselected from the group consisting alkoxy, alkyl, cyano, and hydroxy;Ar₂ is selected from the group consisting of benzofuranyl, benzothienyl,carbazolyl, tetrahydrocarbazolyl, furyl; imidazolyl, 3-methylindazolyl,3-indolyl, 5-indolyl, 1-methyl-3-indolyl, 1-methyl-5-indolyl,3-methyl-5-indolyl, 3-[(dimethylamino)methyl]indolyl,1-[(4-methylphenyl)sulfonyl]indolyl, 3,5-dimethylisoxazolyl, naphthyl,pyrazolyl, 3,5-dimethylpyrazolyl, 1-methylpyrazolyl, 6-oxopyridazinyl,pyridyl, 6-aminopyridyl, 2-cyanopyridyl, pyrimidinyl,2-methoxypyrimidinyl, 2-pyrrolyl, 3-pyrrolyl, quinolinyl, thienyl,3,4-(methylenedioxy)phenyl, and phenyl, wherein the phenyl issubstituted with 0, 1, or 2 substituents selected from the groupconsisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy,cyano, halogen, haloalkoxy, haloalkyl, hydroxy, nitro, —NR_(A)R_(B),(NR_(A)R_(B))alkyl, (NR_(A)R_(B))alkoxy, and phenyl.

Another example of a particular embodiment of the compounds for theinvention is wherein Z is an eight-membered bridged bicyclic ring, forexample

Ar₁ is pyridazinyl, and Ar₂ is as described, either generally orparticularly, and more particularly Ar₂ is phenyl substituted with 0, 1,or 2 substituents selected from the group consisting of alkoxy,alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halogen,haloalkoxy, haloalkyl, hydroxy, nitro, —NR_(A)R_(B), (NR_(A)R_(B))alkyl,(NR_(A)R_(B))alkoxy, and phenyl.

One example of a particular embodiment of the compounds for theinvention is wherein Z is a eight-membered fused bicyclic ring, forexample

Ar₁ is selected from the group consisting of isoxazolyl, oxadiazolyl,oxazolyl, pyrazolyl, pyridazinyl, 4-methylpyridazinyl,5-methylpyridazinyl, pyridyl, 5-cyanopyridyl, pyrimidinyl, thiadiazolyl,thiazolyl, thienyl, and phenyl substituted with 0 or 1 substituentselected from the group consisting alkoxy, alkyl, cyano, and hydroxy;Ar₂ is selected from the group consisting of benzofuranyl, benzothienyl,carbazolyl, tetrahydrocarbazolyl, furyl; imidazolyl, 3-methylindazolyl,3-indolyl, 5-indolyl, 1-methyl-3-indolyl, 1-methyl-5-indolyl,3-methyl-5-indolyl, 3-[(dimethylamino)methyl]indolyl,1-[(4-methylphenyl)sulfonyl]indolyl, 3,5-dimethylisoxazolyl, naphthyl,pyrazolyl, 3,5-dimethylpyrazolyl, 1-methylpyrazolyl, 6-oxopyridazinyl,pyridyl, 6-aminopyridyl, 2-cyanopyridyl, pyrimidinyl,2-methoxypyrimidinyl, 2-pyrrolyl, 3-pyrrolyl, quinolinyl, thienyl,3,4-(methylenedioxy)phenyl, and phenyl, wherein the phenyl issubstituted with 0, 1, or 2 substituents selected from the groupconsisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy,cyano, halogen, haloalkoxy, haloalkyl, hydroxy, nitro, —NR_(A)R_(B),(NR_(A)R_(B))alkyl, (NR_(A)R_(B))alkoxy, and phenyl.

Yet another example of a particular embodiment of the compounds for theinvention is wherein Z is an eight-membered fused bicyclic ring, forexample,

Ar₁ is pyridazinyl; and Ar₂ is as described, or more particularly,phenyl substituted with 0, 1, or 2 substituents selected from the groupconsisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy,cyano, halogen, haloalkoxy, haloalkyl, hydroxy, nitro, —NR_(A)R_(B),(NR_(A)R_(B))alkyl, (NR_(A)R_(B))alkoxy, and phenyl.

Still yet another example of a particular embodiment of the compoundsfor the invention is wherein Z is an eight-membered fused bicyclic ring,for example,

Ar₁ is pyridyl; and Ar₂ is as described, or more particularly, furyl,benzothienyl, or phenyl, wherein the phenyl is substituted with 0, 1, or2 substituents selected from the group consisting of alkoxy,alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halogen,haloalkoxy, haloalkyl, hydroxy, nitro, —NR_(A)R_(B), (NR_(A)R_(B))alkyl,(NR_(A)R_(B))alkoxy, and phenyl. Particularly in this embodiment, Ar₂preferably is heteroaryl or bicyclic heteroaryl when Ar₁ is pyridyl,provided that Ar₂ is not 1-pyrrolyl or 1-indolyl.

Yet another example of a particular embodiment of the compounds for theinvention is wherein Z is an eight-membered fused bicyclic ring, forexample,

Ar₁ is either isoxazolyl, oxadiazolyl, pyrazolyl, pyrimidinyl,thiadiazolyl, or thiazolyl; and Ar₂ is as described, or moreparticularly, furyl or phenyl, wherein the phenyl is substituted with 0,1, or 2 substituents selected from the group consisting of alkoxy,alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halogen,haloalkoxy, haloalkyl, hydroxy, nitro, —NR_(A)R_(B), (NR_(A)R_(B))alkyl,(NR_(A)R_(B))alkoxy, and phenyl.

One example of a particular embodiment of the compounds for theinvention is wherein Z is a eight-membered fused bicyclic ring, forexample

Ar₁ is selected from the group consisting of isoxazolyl, oxadiazolyl,oxazolyl, pyrazolyl, pyridazinyl, 4-methylpyridazinyl,5-methylpyridazinyl, pyridyl, 5-cyanopyridyl, pyrimidinyl, thiadiazolyl,thiazolyl, thienyl, and phenyl substituted with 0 or 1 substituentselected from the group consisting alkoxy, alkyl, cyano, and hydroxy;Ar₂ is selected from the group consisting of benzofuranyl, benzothienyl,carbazolyl, tetrahydrocarbazolyl, furyl; imidazolyl, 3-methylindazolyl,3-indolyl, 5-indolyl, 1-methyl-3-indolyl, 1-methyl-5-indolyl,3-methyl-5-indolyl, 3-[(dimethylamino)methyl]indolyl,1-[(4-methylphenyl)sulfonyl]indolyl, 3,5-dimethylisoxazolyl, naphthyl,pyrazolyl, 3,5-dimethylpyrazolyl, 1-methylpyrazolyl, 6-oxopyridazinyl,pyridyl, 6-aminopyridyl, 2-cyanopyridyl, pyrimidinyl,2-methoxypyrimidinyl, 2-pyrrolyl, 3-pyrrolyl, quinolinyl, thienyl,3,4-(methylenedioxy)phenyl, and phenyl, wherein the phenyl issubstituted with 0, 1, or 2 substituents selected from the groupconsisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy,cyano, halogen, haloalkoxy, haloalkyl, hydroxy, nitro, —NR_(A)R_(B),(NR_(A)R_(B))alkyl, (NR_(A)R_(B))alkoxy, and phenyl.

Another example of a particular embodiment of the compounds for theinvention is an eight-membered fused bicyclic ring, for example whereinZ is

Ar₁ is pyridazinyl, pyrimidinyl, or thiazolyl; and Ar₂ is as described,or more particularly, selected from the group consisting of3,4-(methylenedioxy)phenyl and phenyl wherein the phenyl is substitutedwith 0, 1, or 2 substituents selected from the group consisting ofalkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halogen,haloalkoxy, haloalkyl, hydroxy, nitro, —NR_(A)R_(B), (NR_(A)R_(B))alkyl,(NR_(A)R_(B))alkoxy, and phenyl.

Another example of a particular embodiment of the compounds for theinvention is an eight-membered fused bicyclic ring, for example whereinZ is

Ar₁ is selected from the group consisting of isoxazolyl, oxadiazolyl,oxazolyl, pyrazolyl, pyridazinyl, 4-methylpyridazinyl,5-methylpyridazinyl, pyridyl, 5-cyanopyridyl, pyrimidinyl, thiadiazolyl,thiazolyl, thienyl, and phenyl substituted with 0 or 1 substituentselected from the group consisting alkoxy, alkyl, cyano, and hydroxy;Ar₂ is selected from the group consisting of benzofuranyl, benzothienyl,carbazolyl, tetrahydrocarbazolyl, furyl; imidazolyl, 3-methylindazolyl,3-indolyl, 5-indolyl, 1-methyl-3-indolyl, 1-methyl-5-indolyl,3-methyl-5-indolyl, 3-[(dimethylamino)methyl]indolyl,1-[(4-methylphenyl)sulfonyl]indolyl, 3,5-dimethylisoxazolyl, naphthyl,pyrazolyl, 3,5-dimethylpyrazolyl, 1-methylpyrazolyl, 6-oxopyridazinyl,pyridyl, 6-aminopyridyl, 2-cyanopyridyl, pyrimidinyl,2-methoxypyrimidinyl, 2-pyrrolyl, 3-pyrrolyl, quinolinyl, thienyl,3,4-(methylenedioxy)phenyl, and phenyl, wherein the phenyl issubstituted with 0, 1, or 2 substituents selected from the groupconsisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy,cyano, halogen, haloalkoxy, haloalkyl, hydroxy, nitro, —NR_(A)R_(B),(NR_(A)R_(B))alkyl, (NR_(A)R_(B))alkoxy, and phenyl.

Another example of a particular embodiment of the compounds for theinvention is a seven-membered bridged bicyclic ring, for example whereinZ is

Ar₁ is selected from the group consisting of isoxazolyl, oxadiazolyl,oxazolyl, pyrazolyl, pyridazinyl, 4-methylpyridazinyl,5-methylpyridazinyl, pyridyl, 5-cyanopyridyl, pyrimidinyl, thiadiazolyl,thiazolyl, thienyl, and phenyl substituted with 0 or 1 substituentselected from the group consisting alkoxy, alkyl, cyano, and hydroxy;Ar₂ is selected from the group consisting of benzofuranyl, benzothienyl,carbazolyl, tetrahydrocarbazolyl, furyl; imidazolyl, 3-methylindazolyl,3-indolyl, 5-indolyl, 1-methyl-3-indolyl, 1-methyl-5-indolyl,3-methyl-5-indolyl, 3-[(dimethylamino)methyl]indolyl,1-[(4-methylphenyl)sulfonyl]indolyl, 3,5-dimethylisoxazolyl, naphthyl,pyrazolyl, 3,5-dimethylpyrazolyl, 1-methylpyrazolyl, 6-oxopyridazinyl,pyridyl, 6-aminopyridyl, 2-cyanopyridyl, pyrimidinyl,2-methoxypyrimidinyl, 2-pyrrolyl, 3-pyrrolyl, quinolinyl, thienyl,3,4-(methylenedioxy)phenyl, and phenyl, wherein the phenyl issubstituted with 0, 1, or 2 substituents selected from the groupconsisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy,cyano, halogen, haloalkoxy, haloalkyl, hydroxy, nitro, —NR_(A)R_(B),(NR_(A)R_(B))alkyl, (NR_(A)R_(B))alkoxy, and phenyl.

Another example of a particular embodiment of the compounds for theinvention is a nine-membered fused bicyclic ring, for example wherein Zis

Ar₁ is selected from the group consisting of isoxazolyl, oxadiazolyl,oxazolyl, pyrazolyl, pyridazinyl, 4-methylpyridazinyl,5-methylpyridazinyl, pyridyl, 5-cyanopyridyl, pyrimidinyl, thiadiazolyl,thiazolyl, thienyl, and phenyl substituted with 0 or 1 substituentselected from the group consisting alkoxy, alkyl, cyano, and hydroxy;Ar₂ is selected from the group consisting of benzofuranyl, benzothienyl,carbazolyl, tetrahydrocarbazolyl, furyl; imidazolyl, 3-methylindazolyl,3-indolyl, 5-indolyl, 1-methyl-3-indolyl, 1-methyl-5-indolyl,3-methyl-5-indolyl, 3-[(dimethylamino)methyl]indolyl,1-[(4-methylphenyl)sulfonyl]indolyl, 3,5-dimethylisoxazolyl, naphthyl,pyrazolyl, 3,5-dimethylpyrazolyl, 1-methylpyrazolyl, 6-oxopyridazinyl,pyridyl, 6-aminopyridyl, 2-cyanopyridyl, pyrimidinyl,2-methoxypyrimidinyl, 2-pyrrolyl, 3-pyrrolyl, quinolinyl, thienyl,3,4-(methylenedioxy)phenyl, and phenyl, wherein the phenyl issubstituted with 0, 1, or 2 substituents selected from the groupconsisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy,cyano, halogen, haloalkoxy, haloalkyl, hydroxy, nitro, —NR_(A)R_(B),(NR_(A)R_(B))alkyl, (NR_(A)R_(B))alkoxy, and phenyl.

Specific embodiments contemplated include, but are not limited to,compounds of formula (I), as defined, wherein:

-   3-(6-phenyl-pyridazin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane;-   8-methyl-3-(6-phenyl-pyridazin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane;-   6-methyl-3-(6-phenyl-pyridazin-3-yl)-3,6-diaza-bicyclo[3.2.1]octane;-   3-(6-phenyl-pyridazin-3-yl)-3,8-diaza-bicyclo[4.2.0]octane;-   8-methyl-3-(6-phenyl-pyridazin-3-yl)-3,8-diaza-bicyclo[4.2.0]octane;-   2-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(6-m-tolyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-methyl-5-(6-m-tolyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-[6-(4-methoxy-phenyl)-pyridazin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(6-biphenyl-3-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(6-biphenyl-3-yl-pyridin-3-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;-   2-[6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   2-methyl-5-[6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   3-[5-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-2-yl]-phenylamine;-   5-(6-furan-3-yl-pyridin-3-yl)-hexahydro-pyrrolo[3,4-c]pyrrole;-   2-(6-furan-3-yl-pyridin-3-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(6-benzo[b]thiophen-2-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(6-benzo[b]thiophen-2-yl-pyridin-3-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(5-phenyl-pyridin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-methyl-5-(5-phenyl-pyridin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(2-phenyl-pyrimidin-5-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-methyl-5-(2-phenyl-pyrimidin-5-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   diethyl-(2-{3-[6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenoxy}-ethyl)-amine;-   diethyl-(2-{3-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenoxy}-ethyl)-amine;-   2-(5-phenyl-[1,3,4]thiadiazol-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(3-phenyl-[1,2,4]thiadiazol-5-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-methyl-5-(3-phenyl-[1,2,4]thiadiazol-5-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(1-phenyl-1h-pyrazol-4-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(2-methoxy-biphenyl-4-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(2-methoxy-biphenyl-4-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;-   2-methyl-5-(3-phenyl-isoxazol-5-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   (1S,5S) 3-(6-phenyl-pyridazin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1S,5S)-6-methyl-3-(6-phenyl-pyridazin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5S)-6-(6-phenyl-pyridazin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5S)-3-methyl-6-(6-phenyl-pyridazin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5R) 3-(6-phenyl-pyridazin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5R)-6-methyl-3-(6-phenyl-pyridazin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5R)-3-(6-benzo[1,3]dioxol-5-yl-pyridazin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5R)-3-(6-benzo[1,3]dioxol-5-yl-pyridazin-3-yl)-6-methyl-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5R)-1-{4-[5-(3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-phenyl}-ethanone;-   (1R,5R)-1-{4-[5-(6-methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-phenyl}ethanone;-   6a-methyl-5-(6-m-tolyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-b]pyrrole;-   2-(5-phenyl-thiazol-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-methyl-5-(5-phenyl-thiazol-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   3-(6-Phenyl-pyridazin-3-yl)-3,8-diaza-bicyclo[4.2.0]octane;-   8-(6-Phenyl-pyridazin-3-yl)-3,8-diaza-bicyclo[4.2.0]octane;-   3-Methyl-8-(6-phenyl-pyridazin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane;-   6a-Methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-b]pyrrole;-   2-(6-Phenyl-pyridazin-3-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-3a-carboxylic    acid ethyl ester;-   2,5-Bis-(6-phenyl-pyridazin-3-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-3a-carboxylic    acid ethyl ester;-   (1R,5R)-6-(6-Phenyl-pyridazin-3-yl)-2,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5R)-2-(6-Phenyl-pyridazin-3-yl)-2,6-diaza-bicyclo[3.2.0]heptane;-   Ethyl    2-Methyl-5-(6-phenyl-pyridazin-3-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-3a-carboxylate;-   5-Methyl-2-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyridine;-   1-Benzyl-6a-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-b]pyrrole;-   3-Methyl-6-(6-phenyl-pyridazin-3-yl)-3,6-diaza-bicyclo[3.2.1]octane;-   8-(6-Phenyl-pyridazin-3-yl)-3,8-diaza-bicyclo[4.2.0]octane;-   3-Methyl-8-(6-phenyl-pyridazin-3-yl)-3,8-diaza-bicyclo[4.2.0]octane;-   3-Methyl-8-(6-phenyl-pyridazin-3-yl)-3,8-diaza-bicyclo[4.2.0]octane;-   3-Methyl-8-(6-phenyl-pyridazin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane;-   1,6a-Dimethyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-b]pyrrole;-   2-[6-(4-Bromo-phenyl)-pyridazin-3-yl]-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;-   (1S,5S)-3-[6-(4-Bromo-phenyl)-pyridazin-3-yl]-3,6-diaza-bicyclo[3.2.0]heptane;-   (1S,5S)-3-[6-(4-Bromo-phenyl)-pyridazin-3-yl]-6-methyl-3,6-diaza-bicyclo[3.2.0]heptane;-   3-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-1H-indole;-   3-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-1H-indole;-   (1R,5R)-3-[6-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)-pyridazin-3-yl]-1H-indole;-   (1S,5S)-3-[6-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)-pyridazin-3-yl]-1H-indole;-   (1R,5R)-3-[6-(6-Methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridazin-3-yl]-1H-indole;-   2-[6-(4-Nitro-phenyl)-pyridazin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   2-[6-(2-Nitro-phenyl)-pyridazin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   2-[6-(3-Nitro-phenyl)-pyridazin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-[6-(4-nitro-phenyl)-pyridazin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-[6-(3-nitro-phenyl)-pyridazin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(6-Imidazol-1-yl-pyridazin-3-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(6-Imidazol-1-yl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   (1R,5S)-6-[6-(4-Iodo-phenyl)-pyridazin-3-yl]-3,6-diaza-bicyclo[3.2.0]heptane;-   (1S,5S)-3-[6-(4-Iodo-phenyl)-pyridazin-3-yl]-3,6-diaza-bicyclo[3.2.0]heptane;-   (1S,5S)-3-[6-(4-Iodo-phenyl)-pyridazin-3-yl]-6-methyl-3,6-diaza-bicyclo[3.2.0]heptane;-   2-(5-Methyl-6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-(5-methyl-6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(4-Methyl-6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-(4-methyl-6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(6-o-Tolyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(6-p-Tolyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-[6-(3,5-Dimethyl-phenyl)-pyridazin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(6-Furan-3-yl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(6-Thiophen-3-yl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-(6-thiophen-3-yl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   5-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-1H-indole;-   5-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-1-methyl-1H-indole;-   2-Methyl-5-(6-o-tolyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-(6-p-tolyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-[6-(3,5-Dimethyl-phenyl)-pyridazin-3-yl]-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(6-Furan-3-yl-pyridazin-3-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;-   3-Methyl-8-(6-phenyl-pyridazin-3-yl)-3,8-diaza-bicyclo[4.2.0]octane;-   5-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-1H-indole;-   3-Methyl-5-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-1H-indole;-   2-Methyl-5-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenylamine;-   4-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenylamine;-   4-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-1H-indole;-   2-(6-Benzofuran-2-yl-pyridazin-3-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;-   5-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-pyridin-2-ylamine;-   2-Methyl-5-[6-(1H-pyrrol-3-yl)-pyridazin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-(6-thiophen-2-yl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-[6-(1H-pyrazol-4-yl)-pyridazin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   3-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-9H-carbazole;-   2-(6-Furan-2-yl-pyridazin-3-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-(5-pyrimidin-5-yl-pyridin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-[5-(1H-pyrazol-4-yl)-pyridin-2-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   3-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-3-yl]-benzonitrile;-   2-[5-(2-Methoxy-pyrimidin-5-yl)-pyridin-2-yl]-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;-   2-[5-(3,5-Dimethyl-1H-pyrazol-4-yl)-pyridin-2-yl]-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-[5-(1-methyl-1H-pyrazol-4-yl)-pyridin-2-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   2-[5-(3,5-Dimethyl-isoxazol-4-yl)-pyridin-2-yl]-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;-   6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-[3,3′]bipyridinyl;-   6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-[3,4′]bipyridinyl;-   4-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-3-yl]-benzonitrile;-   6′-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-[3,3′]bipyridinyl-6-ylamine;-   2-Methyl-5-[5-(1H-pyrrol-3-yl)-pyridin-2-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-[5-(1H-pyrrol-2-yl)-pyridin-2-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   6′-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-[3,3′]bipyridinyl-2-carbonitrile;-   2-(5-Furan-3-yl-pyridin-2-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-(5-thiophen-2-yl-pyridin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-(5-thiophen-3-yl-pyridin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(5-Benzofuran-5-yl-pyridin-2-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(5-Furan-2-yl-pyridin-2-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;-   3-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-3-yl]-9H-carbazole;-   5-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-3-yl]-1H-indole;-   4-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-3-yl]-1H-indole;-   2-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-3-yl]-2H-pyridazin-3-one;-   2-(6-Phenyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(6-o-Tolyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(6-m-Tolyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-[6-(3-Methoxy-phenyl)-pyridin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole-   2-[6-(3-Trifluoromethoxy-phenyl)-pyridin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(6-Thiophen-3-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   8-[5-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-2-yl]-quinoline;-   2-(6-Naphthalen-2-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(6-Benzofuran-2-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-(6-o-tolyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-(6-m-tolyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-(6-phenyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-[6-(3-Methoxy-phenyl)-pyridin-3-yl]-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-[6-(3-trifluoromethoxy-phenyl)-pyridin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-[6-(3-nitro-phenyl)-pyridin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-(6-thiophen-3-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   8-[5-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-2-yl]-quinoline;-   2-Methyl-5-(6-naphthalen-2-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   5-[5-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-2-yl]-1H-indole;-   4-[5-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-2-yl]-1H-indole;-   5-[5-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-2-yl]-quinoline;-   (1R,5R)-3-(6-p-Tolyl-pyridazin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5R)-3-(6-o-Tolyl-pyridazin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5R)-3-(6-m-Tolyl-pyridazin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5R)-6-Methyl-3-(6-p-tolyl-pyridazin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5R)-6-Methyl-3-(6-o-tolyl-pyridazin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1S,5S)-5-[6-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)-pyridazin-3-yl]-1H-indole;-   (1S,5S)-5-[6-(6-Methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridazin-3-yl]-1H-indole;-   (1S,5S)-4-[6-(6-Methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridazin-3-yl]-1H-indole;-   (1S,5S)-3-(6-Benzofuran-5-yl-pyridazin-3-yl)-6-methyl-3,6-diaza-bicyclo[3.2.0]heptane;-   (1S,5S)-4-[6-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)-pyridazin-3-yl]-phenylamine;-   (1R,5S)-3-[6-(3-Methyl-3,6-diaza-bicyclo[3.2.0]hept-6-yl)-pyridazin-3-yl]-thiophene;-   (1R,5S)-5-[6-(3-Methyl-3,6-diaza-bicyclo[3.2.0]hept-6-yl)-pyridazin-3-yl]-1H-indole-   (1R,5S)-4-[6-(3-Methyl-3,6-diaza-bicyclo[3.2.0]hept-6-yl)-pyridazin-3-yl]-1H-indole-   3-Methyl-5-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-1H-indazole;-   (1S,5S)-5-[6-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-3-yl]-3-methyl-1H-indazole;-   (1R,5R)-{4-[5-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-phenyl}-dimethyl-amine;-   (1R,5R)-6-Methyl-3-(6-m-tolyl-pyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5R)-6-Methyl-3-(6-p-tolyl-pyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5R)-3-[5-(6-Methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-benzonitrile;-   (1R,5R)-3-[6-(4-Ethyl-phenyl)-pyridin-3-yl]-6-methyl-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5R)-Dimethyl-{4-[5-(6-methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-phenyl}-amine;-   (1R,5R)-3-[6-(3-Methoxy-phenyl)-pyridin-3-yl]-6-methyl-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5R)-3-(6-Benzo[1,3]dioxol-5-yl-pyridin-3-yl)-6-methyl-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5R)-3-[6-(4-Methoxy-phenyl)-pyridin-3-yl]-6-methyl-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5R)-3-[6-(3,4-Dimethoxy-phenyl)-pyridin-3-yl]-6-methyl-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5R)-6-Methyl-3-(6-phenyl-pyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5R)-5-(6-Methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-[2,3′]bipyridinyl;-   (1R,5R)-5-[5-(6-Methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-1H-indole;-   (1S,5S)-5-[5-(6-Methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-1H-indole;-   (1R,5S)-6-(6-Phenyl-pyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5S)-6-(6-m-Tolyl-pyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5S)-3-Methyl-6-(6-phenyl-pyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1R,5S)-5-[5-(3-Methyl-3,6-diaza-bicyclo[3.2.0]hept-6-yl)-pyridin-2-yl]-1H-indole;-   (1S,5S)-5-[6-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-3-yl]-1H-indole;-   (1S,5S)-3-(5-Phenyl-pyridin-2-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1S,5S)-6-Methyl-3-(5-phenyl-pyridin-2-yl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1S,5S)-5-[6-(6-Methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-3-yl]-H-indole;-   2-(4-Phenyl-thiophen-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-(5-phenyl-[1,3,4]thiadiazol-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(2-Phenyl-thiazol-5-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-(2-phenyl-thiazol-5-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(4-Phenyl-thiazol-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Benzyl-5-(6-phenyl pyridazin-3-yl)-octahydropyrrolo[3,4-c]pyrrole;-   2-(6-Phenyl    pyridazin-3-yl)-5-(pyridin-4-ylmethyl)-octahydropyrrolo[3,4-c]pyrrole;-   2-(6-Phenyl    pyridazin-3-yl)-5-(pyridin-2-ylmethyl)-octahydropyrrolo[3,4-c]pyrrole;-   2-(6-Chloropyridin-3-ylmethyl)-5-(6-phenylpyridazin-3-yl)-octahydropyrrolo[3,4-c]pyrrole;-   2-(6-Phenyl    pyridazin-3-yl)-5-(2-pyridin-3-ylethyl)-octahydropyrrolo[3,4-c]pyrrole;-   2-(6-Phenyl    pyridazin-3-yl)-5-(pyridin-3-ylmethyl)-octahydropyrrolo[3,4-c]pyrrole;-   2-Allyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-But-2-enyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Ethyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-(6-Phenyl-pyridazin-3-yl)-5-propyl-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Isopropyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   (3aR,6aR)-5-(5-Phenyl-[1,3,4]oxadiazol-2-yl)-octahydro-pyrrolo[3,4-b]pyrrole;-   2-(5-Phenyl-[1,3,4]oxadiazol-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-[5-(4-Methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   2-[5-(4-Methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;-   2-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-octahydro-pyrrolo[3,4-c]pyrrole;-   6-Methyl-3-(5-phenyl-[1,3,4]oxadiazol-2-yl)-3,6-diaza-bicyclo[3.2.1]octane;-   4-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-biphenyl-2-ol;-   4-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-biphenyl-2-ol;-   Diethyl-(2-{3-[6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenoxy}-ethyl)-amine;-   4-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenol;-   Diethyl-(2-{4-[6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenoxy}-ethyl)-amine;-   (2-{4-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenoxy}-ethyl)-dimethyl-amine;-   3-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenol;-   4-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenol;-   Diethyl-(2-{4-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenoxy}-ethyl)-amine;-   N-{4-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenyl}-methanesulfonamide;-   N-{4-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenyl}-benzamide;-   N-{4-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenyl}-methanesulfonamide;-   N-{4-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenyl}-dimethylaminosulfonamide;-   N-{4-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenyl}-acetamide;-   N-{4-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenyl}-acetamide;-   2-[5-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-yl]-phenol;-   2-[5-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyrimidin-2-yl]-phenol;-   2-(4-Pyridin-3-yl-phenyl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Methyl-5-(4-pyridin-3-yl-phenyl)-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Biphenyl-4-yl-octahydro-pyrrolo[3,4-c]pyrrole;-   2-Biphenyl-4-yl-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;-   1-Methyl-5-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-1H-indole;-   Dimethyl-{5-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-1H-indol-3-ylmethyl}-amine;-   (1S,5S)-6-[6-(6-Methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridazin-3-yl]-2,3,4,9-tetrahydro-1H-carbazole;-   (1R,5S)-5-(3,6-Diaza-bicyclo[3.2.0]hept-6-yl)-2-thiophen-2-yl-nicotinonitrile;-   (1R,5S)-5-(3-Methyl-3,6-diaza-bicyclo[3.2.0]hept-6-yl)-2-thiophen-2-yl-nicotinonitrile;-   (1S,5S)-3-(4-Pyridin-3-yl-phenyl)-3,6-diaza-bicyclo[3.2.0]heptane;-   (1S,5S)-6-Methyl-3-(4-pyridin-3-yl-phenyl)-3,6-diaza-bicyclo[3.2.0]heptane;    and-   (1S,5S)-5-[4-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)-phenyl]-3-methyl-1H-indazole;    or pharmaceutically acceptable salts, esters, amides, and prodrugs    thereof.

Compound names are assigned by using AUTONOM naming software, which isprovided by MDL Information Systems GmbH (formerly known as BeilsteinInformationssysteme) of Frankfurt, Germany, and is part of the CHEMDRAW®ULTRA v. 6.0.2 software suite.

Compounds of the invention may exist as stereoisomers wherein,asymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralelement. The terms “R” and “S” used herein are configurations as definedin IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The inventioncontemplates various stereoisomers and mixtures thereof and arespecifically included within the scope of this invention. Stereoisomersinclude enantiomers and diastereomers, and mixtures of enantiomers ordiastereomers. Individual stereoisomers of compounds of the inventionmay be prepared synthetically from commercially available startingmaterials which contain asymmetric or chiral centers or by preparationof racemic mixtures followed by resolution well-known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and optional liberation of theoptically pure product from the auxiliary as described in Furniss,Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical OrganicChemistry”, 5th edition (1989), Longman Scientific & Technical, EssexCM20 2JE, England, or (2) direct separation of the mixture of opticalenantiomers on chiral chromatographic columns or (3) fractionalrecrystallization methods.

Methods for Preparing Compounds of the Invention

As used in the descriptions of the schemes and the examples, certainabbreviations are intended to have the following meanings: Ac foracetyl; Bu for n-butyl; BINAP for2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; DBU for1,8-diazabicyclo[5.4.0]undec-7-ene; DMSO for dimethylsulfoxide; EtOAcfor ethyl acetate; EtOH for ethanol; Et₃N for triethylamine; Et₂O fordiethyl ether; HPLC for high pressure liquid chromatography; i-Pr forisopropyl; MeOH for methanol; NBS for N-bromosuccinimide; OAc foracetate; Ph for phenyl; t-Bu for tert-butyl; and THF fortetrahydrofuran.

The reactions exemplified in the schemes are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. The described transformations mayrequire modifying the order of the synthetic steps or selecting oneparticular process scheme over another in order to obtain a desiredcompound of the invention, depending on the functionality present on themolecule.

Nitrogen protecting groups can be used for protecting amine groupspresent in the described compounds. Such methods, and some suitablenitrogen protecting groups, are described in Greene and Wuts (ProtectiveGroups In Organic Synthesis, Wiley and Sons, 1999). For example,suitable nitrogen protecting groups include, but are not limited to,tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), benzyl (Bn), acetyl,and trifluoroacetyl. More particularly, the BOC protecting group may beremoved by treatment with an acid such as trifluoroacetic acid orhydrochloric acid. The CBZ and Bn protecting groups may be removed bycatalytic hydrogenation. The acetyl and trifluoroacetyl protectinggroups may be removed by a hydroxide ion.

Pyridazines of general formula (4) and (5), wherein Ar₂ and R₃ are asdefined in formula (I), can be prepared as described in Scheme 1.3,6-Dichloropyridazines can be treated with a boronic acid, palladium(0), and a base to provide monochloropyridazines of general formula (2).Monochloropyridazines of general formula (2) can be treated withdiazabicycles of the present invention and a base to provide pyridazinesof general formula (3), wherein P is a nitrogen protecting group.Pyridazines of general formula (3) can be deprotected to providepyridazines of general formula (4). Pyridazines of general formula (4)can be alkylated using reductive amination methods well-known to thoseof skill in the art to provide pyridazines of general formula (5)wherein R is alkyl.

An alternative procedure for preparing pyridazines of general formula(4) and (5), wherein Ar₂ and R₃ are as defined in formula (I), isexemplified in Scheme 2. 3,6-Dichloropyridazines can be treated withdiazabicycles of the present invention, palladium (0), BINAP, and a baseto provide pyridazines of general formula (8), wherein P is a nitrogenprotecting group. Pyridazines of general formula (8) can be treated witha boronic acid, palladium (0), and a base to provide pyridazines ofgeneral formula (3). Pyridazines of general formula (3) can be processedas described in Scheme 1 to provide pyridazines of general formula (4)and (5).

Pyridines of general formula (14) and (16), wherein Ar₂ and R₃ are asdefined in formula (1), can be prepared as described in Scheme 3.2,5-Dihalopyridines can be treated with palladium (0), BINAP, a base,and diazabicycles of the present invention wherein P is a nitrogenprotecting group to provide 5-diazabicyclo-2-halopyridines of generalformula (11) and 2-diazabicyclo-5-halopyridines of general formula (12).5-Diazabicyclo-2-halopyridines of general formula (11) and2-diazabicyclo-5-halopyridines of general formula (12) can be processedas described in Scheme 1 to provide pyridines of general formula (14)and (16).

An alternative procedure for preparing pyridines of general formula(14), wherein Ar₂ and R₃ are as defined in formula (1), is exemplifiedin Scheme 4. Diazabicycles of the present invention, wherein P is anitrogen protecting group, can be treated with 5-bromopyridine, BINAP,palladium (0), and a base to provide pyridines of general formula (21).Pyridines of general formula (21) can be treated with N-bromosuccinimideto provide bromides of general formula (22). Bromides of general formula(22) can be treated with a boronic acid, palladium (0), and a base toprovide biarylcompounds of general formula (23). Biarylcompounds ofgeneral formula (23) can be processed as described in Scheme 1 toprovide pyridines of general formula (14).

Pyrimidines of general formula (29), wherein Ar₂ and R₃ are as definedin formula (1), can be prepared as described in Scheme 5. Diazabicyclesof the present invention, wherein P is a nitrogen protecting group, canbe treated with 5-bromopyrimidines of general formula (25), BINAP,palladium (0), and a base to provide pyrimidines of general formula(26). Pyrimidines of general formula (26) can be treated withN-bromosuccinimide to provide bromides of general formula (27). Bromidesof general formula (27) can be treated with a boronic acid, palladium(0), and a base to provide biarylcompounds of general formula (28).Biarylcompounds of general formula (28) can be processed as described inScheme 1 to provide pyrimidines of general formula (29).

Compounds of general formula (33), wherein Ar₂, Y₁, Y₂, Y₃, and Y₄ areas defined in formula (1) can be prepared as described in Scheme 6.Diazabicyclic compounds of general formula (1), can be treated with5-membered aromatic heteroaryls of general formula (31), purchasedcommercially or prepared using methodology well-known to those in theart, preferably in the presence of palladium (0), BINAP, and a base toprovide compounds of general formula (32). Compounds of general formula(32) can be processed as described in Scheme 1 to provide compounds ofgeneral formula (33).

An alternate method of preparing compounds of general formula (33),wherein Ar₂, Y₁, Y₂, Y₃, and Y₄ are as defined in formula (1), isdescribed in Scheme 7. Diazabicyclic compounds of general formula (1)can be treated with dihalo-5-membered aromatic heteroaryls of generalformula (35), purchased commercially or prepared using methodologywell-known to those in the art, in the presence of palladium (0), BINAP,and a base to provide monohalo compounds of general formula (36).Monohalo compounds of general formula (36) can be treated with boronicacids, palladium (0), and a base to provide compounds of general formula(32). Compounds of general formula (32) can be processed as described inScheme 1 to provide compounds of general formula (33).

Compounds of general formula (42) and (43), wherein Ar₂ and R₃ are asdefined in formula (1), can be prepared as described in Scheme 8.Diazabicycles of the present invention, wherein P is a nitrogenprotecting group, can be treated with bromides of general formula (38),BINAP, palladium (0), and a base to provide compounds of general formula(39). Compounds of general formula (39) can be treated with iodine andthallium acetate to provide iodo compounds of general formula (40). Iodocompounds of general formula (40) can be treated with a boronic acid,palladium (0), and a base to provide biarylcompounds of general formula(41). Biarylcompounds of general formula (41) can be processed asdescribed in Scheme 1 to provide compounds of general formula (42) and(43).

The compounds and intermediates of the invention may be isolated andpurified by methods well-known to those skilled in the art of organicsynthesis. Examples of conventional methods for isolating and purifyingcompounds can include, but are not limited to, chromatography on solidsupports such as silica gel, alumina, or silica derivatized withalkylsilane groups, by recrystallization at high or low temperature withan optional pretreatment with activated carbon, thin-layerchromatography, distillation at various pressures, sublimation undervacuum, and trituration, as described for instance in “Vogel's Textbookof Practical Organic Chemistry”, 5th edition (1989), by Furniss,Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical,Essex CM20 2JE, England.

The compounds of the invention have at least one basic nitrogen wherebythe compound can be treated with an acid to form a desired salt. Forexample, a compound may be reacted with an acid at or above roomtemperature to provide the desired salt, which is deposited, andcollected by filtration after cooling. Examples of acids suitable forthe reaction include, but are not limited to tartaric acid, lactic acid,succinic acid, as well as mandelic, atrolactic, methanesulfonic,ethanesulfonic, toluenesulfonic, naphthalenesulfonic, carbonic, fumaric,gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic,phosphoric, sulfuric, citric, or hydroxybutyric acid, camphorsulfonic,malic, phenylacetic, aspartic, glutamic, and the like.

Compositions of the Invention

The invention also provides pharmaceutical compositions comprising atherapeutically effective amount of a compound of formula (I) incombination with a pharmaceutically acceptable carrier. The compositionscomprise compounds of the invention formulated together with one or morenon-toxic pharmaceutically acceptable carriers. The pharmaceuticalcompositions can be formulated for oral administration in solid orliquid form, for parenteral injection or for rectal administration.

The term “pharmaceutically acceptable carrier,” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil, safflower oil, sesameoil, olive oil, corn oil and soybean oil; glycols; such a propyleneglycol; esters such as ethyl oleate and ethyl laurate; agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of one skilledin the art of formulations.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally,” as used herein, refers to modes of administration,including intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous, intraarticular injection and infusion.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like, and suitable mixturesthereof), vegetable oils (such as olive oil) and injectable organicesters such as ethyl oleate, or suitable mixtures thereof. Suitablefluidity of the composition may be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions can also contain adjuvants such as preservativeagents, wetting agents, emulsifying agents, and dispersing agents.Prevention of the action of microorganisms can be ensured by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It also can bedesirable to include isotonic agents, for example, sugars, sodiumchloride and the like. Prolonged absorption of the injectablepharmaceutical form can be brought about by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is oftendesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug can depend upon its rateof dissolution, which, in turn, may depend upon crystal size andcrystalline form. Alternatively, a parenterally administered drug formcan be administered by dissolving or suspending the drug in an oilvehicle.

Suspensions, in addition to the active compounds, can contain suspendingagents, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

If desired, and for more effective distribution, the compounds of theinvention can be incorporated into slow-release or targeted-deliverysystems such as polymer matrices, liposomes, and microspheres. They maybe sterilized, for example, by filtration through a bacteria-retainingfilter or by incorporation of sterilizing agents in the form of sterilesolid compositions, which may be dissolved in sterile water or someother sterile injectable medium immediately before use.

Injectable depot forms are made by forming microencapsulated matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides) Depot injectable formulations also are prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation also can be a sterile injectablesolution, suspension or emulsion in a nontoxic, parenterally acceptablediluent or solvent such as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, one or morecompounds of the invention is mixed with at least one inertpharmaceutically acceptable carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and salicylic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay; and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof. In the case of capsules, tablets and pills, the dosageform may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using lactose or milk sugar aswell as high molecular weight polyethylene glycols.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well-known in the pharmaceutical formulatingart. They can optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract in a delayedmanner. Examples of materials useful for delaying release of the activeagent can include polymeric substances and waxes.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers such as cocoa butter,polyethylene glycol or a suppository wax which are solid at ambienttemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. A desired compound ofthe invention is admixed under sterile conditions with apharmaceutically acceptable carrier and any needed preservatives orbuffers as may be required. Ophthalmic formulation, eardrops, eyeointments, powders and solutions are also contemplated as being withinthe scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, animal and vegetable fats, oils,waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, lactose, talc, silicic acid, aluminum hydroxide, calciumsilicates and polyamide powder, or mixtures of these substances. Sprayscan additionally contain customary propellants such aschlorofluorohydrocarbons.

Compounds of the invention also can be administered in the form ofliposomes. As is known in the art, liposomes are generally derived fromphospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals that are dispersed in anaqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes may be used. Thepresent compositions in liposome form may contain, in addition to thecompounds of the invention, stabilizers, preservatives, and the like.The preferred lipids are the natural and synthetic phospholipids andphosphatidylcholines (lecithins) used separately or together.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y., (1976), p 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants. Ophthalmicformulations, eye ointments, powders and solutions are also contemplatedas being within the scope of this invention. Aqueous liquid compositionsof the invention also are particularly useful.

The compounds of the invention can be used in the form ofpharmaceutically acceptable salts, esters, or amides derived frominorganic or organic acids. The term “pharmaceutically acceptable salts,esters and amides,” as used herein, include salts, zwitterions, estersand amides of compounds of formula (1) which are, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation, allergicresponse, and the like, are commensurate with a reasonable benefit/riskratio, and are effective for their intended use.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention or separately by reacting a free base function with a suitableorganic acid.

Representative acid addition salts include, but are not limited toacetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate (isethionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, phosphate, glutamate,bicarbonate, p-toluenesulfonate and undecanoate.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides such as methyl, ethyl, propyl, and butylchlorides, bromides and iodides; dialkyl sulfates such as dimethyl,diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkylhalides such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

Examples of acids which can be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acidand such organic acids as oxalic acid, maleic acid, succinic acid, andcitric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium, and aluminum salts, and the like,and nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, diethylamine, ethylamine and the such as.Other representative organic amines useful for the formation of baseaddition salts include ethylenediamine, ethanolamine, diethanolamine,piperidine, and piperazine.

The term “pharmaceutically acceptable ester,” as used herein, refers toesters of compounds of the invention which hydrolyze in vivo and includethose that break down readily in the human body to leave the parentcompound or a salt thereof. Examples of pharmaceutically acceptable,non-toxic esters of the invention include C₁-to-C₆ alkyl esters andC₅-to-C₇ cycloalkyl esters, although C₁-to-C₄ alkyl esters arepreferred. Esters of the compounds of formula (1) can be preparedaccording to conventional methods. Pharmaceutically acceptable esterscan be appended onto hydroxy groups by reaction of the compound thatcontains the hydroxy group with acid and an alkylcarboxylic acid such asacetic acid, or with acid and an arylcarboxylic acid such as benzoicacid. In the case of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine and an alkyl halide, alkyl trifilate, forexample with methyl iodide, benzyl iodide, cyclopentyl iodide. They alsocan be prepared by reaction of the compound with an acid such ashydrochloric acid and an alkylcarboxylic acid such as acetic acid, orwith acid and an arylcarboxylic acid such as benzoic acid.

The term “pharmaceutically acceptable amide,” as used herein, refers tonon-toxic amides of the invention derived from ammonia, primary C₁-to-C₆alkyl amines and secondary C₁-to-C₆ dialkyl amines. In the case ofsecondary amines, the amine can also be in the form of a 5- or6-membered heterocycle containing one nitrogen atom. Amides derived fromammonia, C₁-to-C₃ alkyl primary amides and C₁-to-C₂ dialkyl secondaryamides are preferred. Amides of the compounds of formula (1) can beprepared according to conventional methods. Pharmaceutically acceptableamides can be prepared from compounds containing primary or secondaryamine groups by reaction of the compound that contains the amino groupwith an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide.In the case of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine,for example with methylamine, diethylamine, piperidine. They also can beprepared by reaction of the compound with an acid such as sulfuric acidand an alkylcarboxylic acid such as acetic acid, or with acid and anarylcarboxylic acid such as benzoic acid under dehydrating conditions aswith molecular sieves added. The composition can contain a compound ofthe invention in the form of a pharmaceutically acceptable prodrug.

The term “pharmaceutically acceptable prodrug” or “prodrug,” as usedherein, represents those prodrugs of the compounds of the inventionwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use.Prodrugs of the invention can be rapidly transformed in vivo to a parentcompound of formula (1), for example, by hydrolysis in blood. A thoroughdiscussion is provided in T. Higuchi and V. Stella, Pro-drugs as NovelDelivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press (1987).

The invention contemplates pharmaceutically active compounds eitherchemically synthesized or formed by in vivo biotransformation tocompounds of formula (1).

Methods of the Invention

Compounds and compositions of the invention are useful for modulatingthe effects of nAChRs, and more particularly α7 nAChRs. In particular,the compounds and compositions of the invention can be used for treatingand preventing disorders modulated by α7 nAChRs. Typically, suchdisorders can be ameliorated by selectively modulating the α7 nAChRs ina mammal, preferably by administering a compound or composition of theinvention, either alone or in combination with another active agent, forexample, as part of a therapeutic regimen.

The compounds of the invention, including but not limited to thosespecified in the examples, possess an affinity for nAChRs, and moreparticularly α7 nAChRs. As α7 nAChRs ligands, the compounds of theinvention can be useful for the treatment and prevention of a number ofα7 nAChR-mediated diseases or conditions.

For example, α7 nAChRs have been shown to play a significant role inenhancing cognitive function, including aspects of learning, memory andattention (Levin, E. D., J. Neurobiol. 53: 633-640, 2002). As such, α7ligands are suitable for the treatment of cognitive disorders including,for example, attention deficit disorder, attention deficit hyperactivitydisorder (ADHD), Alzheimer's disease (AD), mild cognitive impairment,senile dementia, AIDS dementia, Pick's Disease, dementia associated withLewy bodies, and dementia associated with Down's syndrome, as well ascognitive deficits associated with schizophrenia.

In addition, α7-containing nAChRs have been shown to be involved in theneuroprotective effects of nicotine both in vitro (Jonnala, R. B. andBuccafusco, J. J., J. Neurosci. Res. 66: 565-572, 2001) and in vivo(Shimohama, S. et al., Brain Res. 779: 359-363, 1998). Moreparticularly, neurodegeneration underlies several progressive CNSdisorders, including, but not limited to, Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis, Huntington'sdisease, dementia with Lewy bodies, as well as diminished CNS functionresulting from traumatic brain injury. For example, the impairedfunction of α7 nAChRs by β-amyloid peptides linked to Alzheimer'sdisease has been implicated as a key factor in development of thecognitive deficits associated with the disease (Liu, Q.-S., Kawai, H.,Berg, D. K., PNAS 98: 4734-4739, 2001). The activation of α7 nAChRs hasbeen shown to block this neurotoxicity (Kihara, T. et al., J. Biol.Chem. 276: 13541-13546, 2001). As such, selective ligands that enhanceα7 activity can counter the deficits of Alzheimer's and otherneurodegenerative diseases.

Parkinson's disease is characterized by muscular rigidity, tremor, andbradykinesia. Epidemiologic studies have long demonstrated thatcigarette-smoking subjects have lower risk of parkinsonism thannonsmokers (Baron, J. A. Neurology 36: 1490-1496, 1986). Moreover,direct administration of nicotine has been shown to improve tremor inParkinson's patients. At least part of the beneficial effect of nicotineis thought to involve neuroprotection, a feature that is now understoodto be mediated by α7 neuronal nAChRs (Jonnala, R. R., Buccausco, J. J.J. Neurosci. Res. 66: 565-571, 2001).

Schizophrenia is a complex disease that is characterized byabnormalities in perception, cognition, and emotions. Significantevidence implicates the involvement of α7 nAChRs in this disease,including a measured deficit of these receptors in post-mortem patients(Leonard, S. Eur. J. Pharmacol. 393: 237-242, 2000). Deficits in sensoryprocessing (gating) are one of the hallmarks of schizophrenia. Thesedeficits can be normalized by nicotinic ligands that operate at the α7nAChR (Adler L. E. et al., Schizophrenia Bull. 24: 189-202, 1998;Stevens, K. E. et al., Psychopharmacology 136: 320-327, 1998). Thus, α7ligands demonstrate potential in the treatment schizophrenia.

Angiogenesis, a process involved in the growth of new blood vessels, isimportant in beneficial systemic functions, such as wound healing,vascularization of skin grafts, and enhancement of circulation, forexample, increased circulation around a vascular occlusion.Non-selective nAChR agonists like nicotine have been shown to stimulateangiogenesis (Heeschen, C. et al., Nature Medicine 7: 833-839, 2001).Improved angiogenesis has been shown to involve activation of the α7nAChR (Heeschen, C. et al, J. Clin. Invest. 110: 527-536, 2002).Therefore, nAChR ligands that are selective for the α7 subtype offerimproved potential for stimulating angiogenesis with an improved sideeffect profile.

A population of α7 nAChRs in the spinal cord modulate serotonergictransmission that have been associated with the pain-relieving effectsof nicotinic compounds (Cordero-Erausquin, M. and Changeux, J.-P. PNAS98:2803-2807, 2001). The α7 nAChR ligands demonstrate therapeuticpotential for the treatment of pain states, including acute pain,post-surgical pain, as well as chronic pain states includinginflammatory pain and neuropathic pain. Moreover, α7 nAChRs areexpressed on the surface of primary macrophages that are involved in theinflammation response, and that activation of the α7 receptor inhibitsrelease of TNF and other cytokines that trigger the inflammationresponse (Wang, H. et al Nature 421: 384-388, 2003). Therefore,selective α7 ligands demonstrate potential for treating conditionsinvolving inflammation and pain.

The mammalian sperm acrosome reaction is an exocytosis process importantin fertilization of the ovum by sperm. Activation of an α7 nAChR on thesperm cell has been shown to be essential for the acrosome reaction(Son, J.-H. and Meizel, S. Biol. Reproduct. 68: 1348-1353 2003).Consequently, selective α7 agents demonstrate utility for treatingfertility disorders.

Compounds of the invention are particularly useful for treating andpreventing a condition or disorder affecting cognition,neurodegeneration, and schizophrenia. Cognitive impairment associatedwith schizophrenia often limits the ability of patients to normallyfunction, a symptom not adequately treated by commonly availabletreatments, for example, treatment with an atypical antipsychotic.(Rowley, M. et al., J. Med. Chem. 44: 477-501, 2001). Such cognitivedeficit has been linked to dysfunction of the nicotinic cholinergicsystem, in particular with decreased activity at α7 receptors.(Friedman, J. I. et al., Biol Psychiatry, 51: 349-357, 2002). Thus,activators of α7 receptors can provide useful treatment for enhancingcognitive function in schizophrenic patients who are being treated withatypical antipsychotics. Accordingly, the combination of an α7 nAChRligand and an atypical antipsychotic would offer improved therapeuticutility. Specific examples of suitable atypical antipsychotics include,but are not limited to, clozapine, risperidone, olanzapine, quietapine,ziprasidone, zotepine, iloperidone, and the like.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the invention can be employed in pureform or, where such forms exist, in pharmaceutically acceptable salt,ester, amide or prodrug form. Alternatively, the compound can beadministered as a pharmaceutical composition containing the compound ofinterest in combination with one or more pharmaceutically acceptablecarriers. The phrase “therapeutically effective amount” of the compoundof the invention means a sufficient amount of the compound to treatdisorders, at a reasonable benefit/risk ratio applicable to any medicaltreatment. It will be understood, however, that the total daily usage ofthe compounds and compositions of the invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well-known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered toa human or lower animal range from about 0.10 mg/kg body weight to about1 g/kg body weight. More preferable doses can be in the range of fromabout 0.10 mg/kg body weight to about 100 mg/kg body weight. If desired,the effective daily dose can be divided into multiple doses for purposesof administration. Consequently, single dose compositions may containsuch amounts or submultiples thereof to make up the daily dose.

The compounds and processes of the invention will be better understoodby reference to the following examples and reference examples, which areintended as an illustration of and not a limitation upon the scope ofthe invention.

EXAMPLES

Examples 1-25, entitled “Diamine Cores”, describe diamine moieties thatcan be are used as referenced in the Examples to prepare compoundsidentified in Examples 31-110, 114-128, 131-188, 191-197, 204-213,225-240, and 243-320. General procedures for coupling the3-chloro-6-phenylpyridazine, deprotecting the resulting compound,methylating the amine nitrogen, and preparing a salt of the compoundobtained thereof, as described in the Examples, are described in Example31, and additional methods are further described in later Examples.

Diamine Cores Example 1 3,8-Diaza-bicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester Example 1A 5-Oxo-pyrrolidine-2-carboxylic acid methylester

To a solution of DL-pyroglutamic acid (50 g, 0.387 mol) in 157 mL CH₃OH(3.87 mol) and 100 mL toluene was added concentrated H₂SO₄ (2.5 mL).This mixture was warmed to reflux and allowed to stir for 16 h. Sincestarting material remained, another 4 mL concentrated H₂SO₄ was addedand the mixture stirred at reflux for an additional 24 h then was cooledto ambient temperature and 20% aqueous NaOH was added to bring thesolution to pH ˜6. The mixture was concentrated under reduced pressureand the residue was dissolved in CH₂Cl₂, filtered through Celite®diatomaceous earth, concentrated and purified via Kugelrohrdistillation. The resulting material was carried on directly to the nextreaction.

Example 1B 1-Benzyl-5-oxo-pyrrolidine-2-carboxylic acid methyl ester

To a slurry of NaH (22 g of 60% NaH in mineral oil, 0.55 mol) in 400 mLbenzene was added the product of Example 1A (0.387 mol) in 100 mLbenzene dropwise via addition funnel. The mixture stirred for 30 minutesafter the addition was complete, then was warmed to reflux and allowedto stir for 1.5 h. The reaction was cooled to 45° C. and stirred for 16h. A portion of benzyl bromide (45 mL, 0.38 mol) was added, the mixturewas warmed to reflux and an additional amount of benzyl bromide wasadded (45 mL, 0.38 mol). This solution stirred for 24 h at reflux, thenwas cooled to ambient temperature, filtered through Celite® diatomaceousearth and the residue was washed with CH₂Cl₂. The combined filtrateswere concentrated under reduced pressure and excess benzyl bromide wasremoved via distillation. The distillation residue was purified viacolumn chromatography (SiO₂, 75% hexanes-EtOAc) to give 46.6 g of thetitle compound (0.2 mol, 52% yield). MS (DCl/NH₃) m/z 234 (M+H)⁺.

Example 1C 1-Benzyl-5-ethoxy-2-methoxycarbonyl-3,4-dihydro-2H-pyrroliumtetrafluoroborate

The product of Example 1B (46.6 g, 0.2 mol) in 200 mL CH₂Cl₂ was addedvia addition funnel to a solution of Meerwein's reagent (Et₃O⁺BF₄ ⁻)(Aldrich, 200 mL of 1 M solution in CH₂Cl₂, 0.2 mol) at ambienttemperature. The reaction mixture stirred for 18 h then was concentratedand the residue was determined to be a 1.8:1 mixture of startingmaterial to product. This mixture was carried on to the next stepwithout further purification.

Example 1D 1-Benzyl-5-nitromethylene-pyrrolidine-2-carboxylic acidmethyl ester

To the mixture obtained in Example 1C (0.2 mol) in 130 mL CH₂Cl₂ atambient temperature was added Et₃N (33.5 mL, 0.24 mol) followed byCH₃NO₂ (13 mL, 0.24 mol). The mixture stirred at ambient temperature for8 h then was diluted with CH₂Cl₂, the layers were separated and theorganic layer was washed with 20 mL 5% H₂SO₄ and 20 mL brine. Theorganic layer was dried over anhydrous Na₂SO₄, concentrated and purifiedvia column chromatography (SiO₂, 50% hexanes-EtOAc) to give 10.2 g ofthe title compound (36.9 mmol). MS (DCl/NH₃) m/z 277 (M+H)⁺.

Example 1E 8-Benzyl-3,8-diaza-bicyclo[3.2.1]octan-2-one

The product of Example 1D (10.2 g, 36.9 mmol) and 5% Pt/C (2 g) in 200mL CH₃OH was shaken under a 30 psi atmosphere of H₂ at ambienttemperature for 24 h. The mixture was then filtered through Celite®diatomaceous earth, and concentrated to give 2.88 g (13.3 mmol, 36%) ofthe title. MS (DCl/NH₃) m/z 217 (M+H)⁺.

Example 1F 8-Benzyl-3,8-diaza-bicyclo[3.2.1]octane

The product of Example 1E (2.88 g, 13.3 mmol) in 40 mL THF was added viacannula to a mixture of LiAlH₄ (1.52 g, 39.9 mmol) in 40 mL THF at 0° C.After the addition was complete, the reaction mixture was allowed towarm to ambient temperature and stir for 2 h. The mixture was warmed toreflux and stirred for 1 h. The reaction was cooled to 0° C. then 1.5 mLH₂O, 1.5 mL 15% NaOH and 4.5 mL H₂O were added sequentially to quenchthe reaction. The material was filtered, the residue was washed withEtOAc, and the filtrate was concentrated under reduced pressure andcarried on directly to the next reaction. MS (DCl/NH₃) m/z 203 (M+H)⁺.

Example 1G1-(8-Benzyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-2,2,2-trifluoro-ethanone

To the product of Example 1F (2.0 g, 9.8 mmol) in 50 mL CH₂Cl₂ was addedEt₃N (7.0 mL, 50 mmol). The mixture was cooled to 0° C. andtrifluoroacetic anhydride (3.53 mL, 25 mmol) was added. The ice-bath wasremoved after the addition was complete and the reaction stirred for 16h at ambient temperature. The mixture was concentrated under reducedpressure and purified by column chromatography (SiO₂, 50% hexanes-EtOAc)to give 2.5 g of the title compound (8.4 mmol, 86% yield). MS (DCl/NH₃)m/z 299 (M+H)⁺.

Example 1H3-(2,2,2-Trifluoro-acetyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

To the product of Example 1G (2.5 g, 8.4 mmol) in 20 mL EtOAc, was addeddi-tert-butyl dicarbonate (2.0 g, 9.22 mmol) and Pd/C (10 wt %, 0.25 g).This mixture was placed under 1 atm. of H₂ via balloon and was allowedto stir for 48 h. The reaction mixture was filtered, concentrated underreduced pressure and purified via column chromatography (SiO₂, 50%hexanes-EtOAc) to give 2 g of the title compound (6.5 mmol, 77% yield).MS (DCl/NH₃) m/z 253 (M+H)⁺.

Example 1I 3,8-Diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butylester

To the product of Example 1H (2.0 g, 6.5 mmol) in 57 mL CH₃OH and 11 mLH₂O was added 2.8 g K₂CO₃ (20.3 mmol). The mixture stirred for 16 h atambient temperature then was filtered, concentrated under reducedpressure and purified via column chromatography (SiO₂, 50%hexanes-EtOAc) to give 1.2 g of the title compound (5.65 mmol, 87%yield). MS (DCl/NH₃) m/z 213 (M+H)⁺.

Example 2 3,6-Diaza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butylester Example 2A tert-Butyl 2-Azabicyclo[2.2.1]hept-5-en-2-carboxylate

Aqueous formalin (37%, 114 mL, 1.41 mol) was added to a well-stirredsolution of NH₄Cl (85.0 g, 1.59 mol) in water (250 mL). Freshlydistilled cyclopentadiene (170 g, 2.58 mol) was added all at once, andthe mixture was stirred vigorously at ambient temperature for 17 h. Thelower, aqueous phase was separated, and was treated with di-t-butyldicarbonate (172 g, 0.78 mol). Aqueous 1M NaOH (100 mL) was added toadjust the pH to ˜8, and the mixture was stirred for 7 h at ambienttemperature with addition of solid NaOH (40 g total) to maintain pH ˜8.The mixture was extracted with hexanes (2×200 mL), and the combinedorganic phase was washed with brine (50 mL), dried over MgSO₄, andconcentrated under vacuum. The residue was distilled under vacuum toprovide the title compound (bp 80-92° C./10 Torr) as a pale yellowliquid that crystallized on cooling (123 g, 0.63 mol, 45% yield). ¹H NMR(CDCl₃, 300 MHz) δ 1.44 (s, 9H), 1.57 (m, 2H), 2.63 (m, 1H), 3.16 (br s,1H), 3.31 (dd, J=9, 3 Hz, 1H), 4.55-4.73 (br m, 1H), 6.25-6.41 (br m,2H). MS (DCl/NH₃) m/z 196 (M+H)⁺.

Example 2B 2,4-Diformyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Through a solution of Example 2A (0.57 g, 2.9 mmol) in 1.5 mL aceticacid and 25 mL CH₂Cl₂ at −78° C. was bubbled O₃ until the solutionturned blue. O₂ was then flushed through the system for 10 min afterwhich dimethylsulfide (0.54 mL, 7.30 mmol) was added. The mixture wasslowly warmed to 20° C. and allowed to stir for 18 h. The solution wasconcentrated and the crude product was carried on directly to the nextreaction. MS (DCl/NH₃) m/z 228 (M+H)⁺.

Example 2C 3-Benzyl-3,6-diaza-bicyclo[3.2.1]octane-6-carboxylic acidtert-butyl ester

To a solution of the crude product of Example 2B (2.92 mmol) in CH₃OH at0° C. was added benzylamine (0.35 mL, 3.21 mmol) and NaCNBH₃ (1.83 g,29.2 mmol). The ice-bath was removed and the mixture stirred at 20° C.for 24 h. The solution was cooled to 0° C. and 10 mL EtOAc and 10 mL H₂Owere added followed by 5 mL of saturated, aqueous NaHCO₃. The layerswere separated and the aqueous layer was extracted with 10 mL EtOAc. Thecombined organic layers were washed with 5 mL H₂O followed by 5 mLbrine, then were dried over anhydrous Na₂SO₄. The mixture was filteredand the filtrate was concentrated and purified via flash columnchromatography to give 0.68 g (2.25 mmol, 77% two-step yield) of thetitle compound. ¹H NMR (CH₃OH-d₄, 300 MHz) δ 1.37 and 1.51 (s, rotamers,9H), 1.46 (m, 1H), 1.57 (dd, J=11.2, 7.46 Hz, 1H), 1.88 (m, 1H), 1.97(m, 1H), 2.32 (m, 2H), 2.82 (m, 1H), 3.02 (m, 1H), 3.52 (m, 3H), 3.91(m, 1H), 7.20 (m, 1H), 7.27 (m, 4H); MS (DCl/NH₃) m/z 303 (M+H)⁺.

Example 2D 3,6-Diaza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butylester

To the product of Example 2C (0.553 g, 1.83 mmol) in 50 mL CH₃OH wasadded 111 mg Pd(OH)₂/C (20 wt %). The mixture was put under 60 psi ofH₂, warmed to 50° C. and allowed to stir for 36 h. The solution was thencooled to 20° C., filtered through Celite® diatomaceous earth, andconcentrated to give the desired product. ¹H NMR (CH₃OH-d₄, 300 MHz) δ1.46 and 1.48 (s, rotamers, 9H), 1.78 (dd, J=11.2, 5.43 Hz, 1H), 1.91(m, 1H), 2.28 (m, 1H), 2.61 (d, J=12.9 Hz, 1H), 2.82 (m, 3H), 3.41 (m,2H), 3.93 (m, 1H); MS (DCl/NH₃) m/z 213 (M+H)⁺.

Example 3 3,8-Diaza-bicyclo[4.2.0]octane-8-carboxylic acid tert-butylester Example 3A 3-Oxo-piperidine-1,4-dicarboxylic acid 1-tert-butylester 4-ethyl ester

A mixture of commercially availableethyl-N-benzyl-3-oxo-4-piperidinecarboxylate hydrochloride (Aldrich,75.4 g, 0.25 mol), di-t-butyl dicarbonate (58.5 g, 0.27 mol), Et₃N (36mL, 0.26 mol), and Pd(OH)₂/C (7.5 g, 50% in H₂O) in 660 mL EtOH was putunder 60 psi of H₂ and was shaken for 25 min. The mixture was thenfiltered and the filtrate was concentrated under reduced pressure toprovide the title compound which was used in the next step withoutfurther purification. MS (DCl/NH₃) m/z 272 (M+H)⁺.

Example 3B5-((1R)-1-Phenyl-ethylamino)-3,6-dihydro-2H-pyridine-1,4-dicarboxylicacid 1-tert-butyl ester 4-ethyl ester

A mixture of the product of Example 3A (72 g, 0.265 mol) andD-(+)-α-methylbenzylamine (Aldrich, 35.9 mL, 0.279 mol) in 750 mL oftoluene was combined in a 1 L, round-bottom flask equipped with aDean-Stark trap. The mixture was refluxed for 36 h with water beingremoved via the Dean-Stark trap. After cooling to ambient temperature,the solution was concentrated and redissolved in EtOAc. Filtrationthrough silica gel and Celite® diatomaceous earth gave the crude titlecompound which was carried on directly to the next reaction. MS(DCl/NH₃) m/z 375 (M+H)⁺.

Example 3C 3-((1R)-1-Phenyl-ethylamino)-piperidine-1,4-dicarboxylic acid1-tert-butyl ester 4-ethyl ester

To a mixture of the product of Example 3B (0.265 mol), NaBH(OAc)₃ (280.8g, 1.33 mol), and 200 g of 4 Å powdered molecular sieves in 900 mLtoluene in a 3-neck round bottom flask equipped with an internalthermometer, mechanical stirrer and addition funnel at 0° C. was addedacetic acid (303 mL, 5.3 mol) dropwise via the addition funnel. Afterthe addition was complete, the mixture was allowed to warm to ambienttemperature and stir for 16 h. The reaction was filtered andconcentrated under reduced pressure to remove as much of the acetic acidas possible. The residue was dissolved in 750 mL EtOAc and 500 mLsaturated aqueous NaHCO₃ solution was added slowly to neutralize theresidual acid. The layers were separated and the aqueous layer wasextracted with 2×100 mL EtOAc. The combined organics were dried overNa₂SO₄ and concentrated under reduced pressure to give the titlecompound which was carried on to the next reaction without furtherpurification. MS (DCl/NH₃) m/z 377 (M+H)⁺.

Example 3D4-Hydroxymethyl-3-((1R)-1-phenyl-ethylamino)-piperidine-1-carboxylicacid tert-butyl ester

To a slurry of LiAlH₄ (0.292 mol) in 1 L tetrahydrofuran at 0° C. wasadded the product of Example 3C (0.265 mol) dropwise via additionfunnel. The ice-bath was removed after the addition was complete and themixture stirred at ambient temperature for 1 h. The reaction wasquenched by the slow addition of approximately 100 g Na₂SO₄.10H₂O(excess). The mixture stirred for 16 h then was filtered, concentratedunder reduced pressure and purified via column chromatography (SiO₂, 33%hexanes-EtOAc) to give 76.5 g of the mixture of isomers (0.23 mol, 86%).MS (DCl/NH₃) m/z 335 (M+H)⁺.

Example 3E8-((1R)-1-Phenyl-ethyl)-3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acidtert-butyl ester

To the mixture of isomers from Example 3D (76.5 g, 0.23 mol) in 1.1 L oftetrahydrofuran at 0° C. was added Et₃N (95.8 mL, 0.687 mol) followed bymethanesulfonyl chloride (23 mL, 0.30 mol). The ice-bath was removedafter the additions were complete and the reaction was allowed to warmto ambient temperature and stirred for 1 h. Cs₂CO₃ (excess) was addedand the mixture was warmed to 60° C. and stirred for 16 h. The reactionwas cooled to ambient temperature, filtered, and the filtrate was washedwith 2×100 mL H₂O. The layers were separated and the aqueous layer wasextracted with 2×100 mL EtOAc. The combined organics were dried overNa₂SO₄ and concentrated under reduced pressure. The material waspurified and the isomers separated via column chromatography (SiO₂, 50%hexanes-EtOAc) to give 30.65 g of the major isomer((1S,6R)-3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butylester (97 mmol, 42%) and 16.5 g of the minor isomer((1R,6S)-3,8-diaza-bicyclo[4.2.0]-octane-3-carboxylic acid tert-butylester (52 mmol, 23%). MS (DCl/NH₃) m/z 317 (M+H)⁺.

Example 3F(1R,6S)-8-((1R)-1-Phenyl-ethyl)-3,8-diaza-bicyclo[4.2.0]octane

To the minor isomer product of Example 3E (9.3 g, 29.4 mmol) in 40 mLCH₂Cl₂ at 0° C. was added 20 mL trifluoroacetic acid. The ice bath wasremoved after the addition and the mixture stirred at ambienttemperature for 3 h then was concentrated under reduced pressure and theresidue was purified via column chromatography (SiO₂, 1% NH₄OH:9%CH₃OH:90% CH₂Cl₂) to give the title compound. MS (DCl/NH₃) m/z 217(M+H)⁺.

Example 3G2,2,2-Trifluoro-1-[(1R,6S)-8-(1-phenyl-ethyl)-3,8-diaza-bicyclo[4.2.0]oct-3-yl]-ethanone

To the product of Example 3F (29.4 mmol) in 210 mL tetrahydrofuran (THF)at −30° C. was added triethylamine (5.15 mL, 36.8 mmol) followed bytrifluoroacetic anhydride (TFAA, 4.36 mL, 30.9 mmol). The mixture waswarmed to −10° C. and stirred for 30 min. The reaction was quenched with50 mL saturated, aqueous NaHCO₃ then was diluted with 100 mL H₂O and 100mL EtOAc. The layers were separated and the aqueous layer was extracted2×50 mL EtOAc. The combined organic layers were dried over Na₂SO₄,filtered through silica gel and Celite® diatomaceous earth with EtOAcand the filtrate was concentrated under reduced pressure to give 8.8 gof the title compound (28.2 mmol, 96% two-step yield). MS (DCl/NH₃) m/z313 (M+H)⁺.

Example 3H(1R,6S)-3-(2,2,2-Trifluoro-acetyl)-3,8-diaza-bicyclo[4.2.0]octane-8-carboxylicacid tert-butyl ester

A mixture of the product of Example 3G (8.8 g, 28.2 mmol), di-t-butyldicarbonate (6.15 g, 28.2 mmol), and 2.21 g of 20% Pd(OH)₂/C in 100 mLCH₃OH was shaken under 60 psi of H₂ for 5 h at 50° C. then for 9.5 h atambient temperature. The reaction was filtered and concentrated underreduced pressure. ¹H-NMR indicated the presence of a bis-di-t-butyldicarbamide-3,8-diaza-bicyclo[4.2.0]octane side product which carried onto the next step along with the crude product. MS (DCl/NH₃) m/z 326(M+NH₄)⁺.

Example 3I (1R,6S)-3,8-Diaza-bicyclo[4.2.0]octane-8-carboxylic acidtert-butyl ester

To the crude product of Example 3H (˜28.2 mmol) in 140 mL CH₃OH and 30mL H₂O was added 4.7 g K₂CO₃ (33.8 mmol). The mixture stirred at ambienttemperature for 16 h then was diluted with a 100 mL of a solution of 1%NH₄OH:9% CH₃OH:90% CH₂Cl₂ and filtered through Celite® diatomaceousearth and silica gel. The filtrate was concentrated under reducedpressure and purified via column chromatography (SiO₂, 1% NH₄OH:9%CH₃OH:90% CH₂Cl₂) to give 3.3 g of the title compound (15.6 mmol, 55%yield). MS (DCl/NH₃) m/z 213 (M+H)⁺.

Example 4 (1S,6R)-3,8-Diaza-bicyclo[4.2.0]octane-8-carboxylic acidtert-butyl ester

The major isomer from Example 3E was processed according to theprocedures of Examples 3F, 3G, 3H, and 3I to provide the title compound:MS (DCl/NH₃) m/z 213 (M+H)⁺

Example 5 t-Butyl 3,6-diazabicyclo[3.2.1]octane-3-carboxylate Example 5A1-(3-Benzyl-3,6-diazabicyclo[3.2.1]oct-6-yl)-2,2,2-trifluoro-ethanone

To the product of Example 2C (0.68 g, 2.25 mmol) in 7 mL CH₂Cl₂ at 0° C.was added 3.5 mL trifluoroacetic anhydride. The ice-bath was removed andthe mixture stirred at 20° C. fr 2 h. The solution was then concentratedand the residue was dissolved in THF (15 mL). Triethylamine (0.41 mL,2.92 mmol, 1.3 eq) was added, followed by trifluoroacetic anhydride(0.38 mL, 2.70 mmol, 1.2 eq). The mixture was stirred for 15 min at 0°C. then was allowed to warm to 20° C. at which temperature it stirredfor 18 h. The solution was concentrated and purified via flash columnchromatography to give quantitative yield of the desiredtrifluoroacetamide (0.67 g, 2.25 mmol, 100% two-step yield). ¹H NMR(CH₃OH-d₄, 300 MHz)

1.97 (m, 1H), 2.06 (m, 1H), 2.12 (m, 1H), 2.84 (m, 1H), 3.41 (m, 2H),3.61 (m, 2H), 3.82 (m, 1H), 4.32 (m, 2H), 4.64 (m, 1H), 7.48 (m, 5H); MS(DCl/NH₃) m/z 299 (M+H)⁺.

Example 5B t-Butyl 3,6-Diazabicyclo[3.2.1]octane-6-carboxylate

To the product of Example 5A (0.67 g, 2.25 mmol) and Boc₂O (0.55 g, 2.51mmol, 1.1 eq) in 50 mL CH₃OH was added 135 mg Pd(OH)₂/C (20 wt %). Themixture was put under 60 psi of H₂ and allowed to stir for 18 h. Thesolution was then filtered through Celite®, and concentrated. Theresidue was dissolved in CH₃OH (10 mL) and H₂O (2 mL) and treated withK₂CO₃ (0.5 g, 3.62 mmol, 1.6 eq). The mixture stirred for 20 h and thenconcentrated. The residue was taken up in a mixture of 90% CH₂Cl₂, 9%CH₃OH and 1% NH₄OH and filtered through diatomaceous earth and silicagel. The filtrate was concentrated to provide 0.47 g of the titlecompound (2.21 mmol, 98% yield). ¹H NMR (CH₃OH-d₄, 300 MHz) δ 1.42 (m,1H), 1.46 (s, 9H), 1.89 (m, 2H), 2.58 (m, 1H), 3.00 (m, 2H), 3.12 (m,2H), 3.78 (m, 1H), 3.84 (dd, J=12.88, 3.39 Hz, 1H), 3.92 (br d, J=13.9Hz, 1H); MS (DCl/NH₃) m/z 213 (M+H)⁺.

Example 6 Hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butylester Example 6A 5-Benzyl-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione

To the maleimide (80.4 g, 0.83 mol) in 1.5 L of CH₂Cl₂ in a 3-neck, 3-Lround bottom flask equipped with an addition funnel, internalthermometer, and N₂ inlet at 0° C. was added trifluoroacetic acid (TFA)(6.4 mL, 83 mmol). Benzyl(methoxymethyl)trimethylsilylmethylamine (261g, 1.1 mol) in 500 mL CH₂Cl₂ was added dropwise via addition funnel over3 hours with the reaction temperature being maintained below 5° C. Afterthe addition was complete, the mixture was allowed to warm slowly toambient temperature and then was stirred for 16 h. The mixture wasconcentrated and the residue was dissolved in 500 mL CH₂Cl₂ and waswashed with 2×50 mL saturated NaHCO₃. The layers were separated and theaqueous layer was extracted 2×25 mL CH₂Cl₂. The combined organics werewashed with 25 mL brine, dried over saturated, aqueous Na₂SO₃, andconcentrated under reduced pressure to give the title compound which wascarried on to the next step without further purification. MS (DCl/NH₃)m/z 231 (M+H)⁺.

Example 6B 5-Benzyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acidtert-butyl ester

To a slurry of LiAlH₄ (25 g, 0.63 mol) in 1 L THF at 0° C. in a 3-Lround bottom flask equipped with an addition funnel and an N₂ inlet, wasadded 48 g (0.19 mmol) of the crude product of Example 6A (0.21 mol) in500 mL THF dropwise via the addition funnel over 3 h. After the additionwas complete, the ice-bath was removed and the mixture stirred atambient temperature for 30 min before being warmed to reflux and stirredfor 4 h. The reaction was cooled to 0° C. and quenched by the slowaddition of Na₂SO₄.10H₂O (excess). This mixture stirred for 16 h atambient temperature then was filtered and the residue was washed withEtOAc. The combined filtrates were concentrated and the residue wasdissolved in 500 mL THF. Di-t-butyl dicarbonate (46 g, 0.21 mol) and 100mL saturated, aqueous NaHCO₃ were added and the mixture stirred for 16 hat ambient temperature. The reaction was quenched with 50 mL H₂O and 250mL EtOAc was added. The layers were separated, the aqueous layer wasextracted 3×50 mL EtOAc, and the combined organic layers were dried overNa₂SO₄ and concentrated under reduced pressure. Purification via columnchromatography (SiO₂, 50% hexanes-EtOAc) gave 33.4 g of the titlecompound (0.11 mol, 53% yield). MS (DCl/NH₃) m/z 303 (M+H)⁺.

Example 6C Hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butylester

To the product of Example 6B (107.8 g, 0.356 mol) in 250 mL CH₃OH wasadded 10.8 g of 20% Pd(OH)₂/C, wet. This mixture was hydrogenated for2.5 h under 60 psi of H₂ at 50° C. The mixture was filtered andconcentrated to give 74 g of the title compound (0.35 mmol, 98% yield).MS (DCl/NH₃) m/z 213 (M+H)⁺.

Example 7 Benzyl (1S,5S)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylateExample 7A (2,2-Dimethoxy-ethyl)-carbamic acid benzyl ester

Benzyl chloroformate (Aldrich, 231.3 g, 1.3 mol) was added gradually toa mixture of aminoacetaldehyde dimethyl acetal (Aldrich, 152.0 g, 1.3mol) in toluene (750 mL) and aqueous NaOH (72.8 g, 1.82 mol; in 375 mLof water) at 10-20° C. After the addition was complete, the mixture wasstirred at ambient temperature for 4 h. The layers were separated andthe organic layer was washed with brine (2×100 mL) and concentratedunder reduced pressure to provide the title compound as an oil (281.5 g,90% yield). ¹H NMR (CDCl₄, 300 MHz) δ 3.33 (t, J=6.0 Hz, 2H), 3.39 (s,6H), 4.37 (t, J=6.0 Hz, 1H), 5.11 (s, 2H), 7.30 (m, 5H); MS (DCl/NH₃)m/z 257 (M+NH₄)⁺, 240 (M+H)⁺.

Example 7B Allyl-(2,2-dimethoxy-ethyl)-carbamic acid benzyl ester

The product of Example 7A (281.0 g, 1.18 mol) in dry toluene (1.0 L) wastreated with powdered KOH (291.2 g, 5.20 mol) and triethylbenzylammoniumchloride (Aldrich, 4.4 g, 0.02 mol). A solution of allyl bromide(Aldrich, 188.7 g, 1.56 mol) in toluene (300 mL) was then added dropwiseover 1 hour at 20-30° C. The mixture was stirred for ˜18 h at ambienttemperature and then water (300 mL) was added over 20 minutes at 20-30°C. The layers were separated and the aqueous phase was extracted withtoluene (2×300 mL). The organic phases were combined, washed with brine(2×100 mL), dried (K₂CO₃), filtered and the filtrate concentrated underreduced pressure to provide the title compound as an oil (315.6 g, 1.13mol, 96%, yield). ¹H NMR (MeOH-d₄, 300 MHz) δ 3.32 (s, 3H) 3.37 (m, 5H),3.97 (d, J=5.4 Hz, 2H), 4.50-4.40 (m, 1H), 5.15 (m, 4H), 5.75 (m, 1H),7.23 (m, 5H); MS (DCl/NH₃) m/z 297 (M+NH₄)⁺, 280 (M+H)⁺.

Example 7C Allyl-(2-oxo-ethyl)-carbamic acid benzyl ester

The product of Example 7B (314.0 g, 1.125 mol) was treated with formicacid (88%, 350 mL) at room temperature and allowed to stir for 15 hours.Most of the formic acid was removed by concentration under reducedpressure at 40-50° C. The residue was extracted with ethyl acetate(3×500 mL). The extracts were combined and washed with brine until thewash had a pH=6-7. The organic phase was concentrated under reducedpressure to provide the title compound as a slightly yellow oil (260.0g, 1.12 mmol 99% yield). ¹H NMR (CDCl₃, 300 MHz) δ 3.20 (m, 1H), 3.97(m, 2H), 4.10 (m, 1H), 5.10 (m, 4H), 5.75 (m, 1H), 7.45 (m, 5H), 9.50(d, J=6.4 Hz, 1H); MS (DCl/NH₃) m/z 234 (M+H)⁺.

Example 7D Allyl-(2-hydroxyimino-ethyl)-carbamic acid benzyl ester

The product of Example 7C (260 g, 1.12 mol) in acetonitrile (1.5 L) wastreated with sodium acetate trihydrate (170.6 g, 4.41 mol, in 0.75 Ldistilled water) and NH₂OH.hydrochloride (98.0 g, 4.41 mol) under N₂.The mixture was stirred at ambient temperature over 20 hours. Thevolatiles were removed under reduced pressure and the residue wasextracted with ethyl acetate (2×750 mL). The combined organic phaseswere washed with brine until the wash had a pH=7. The organic phase wasconcentrated under reduced pressure to provide the title compound as anoil (271 g, 1.09 mol, 98% yield). ¹H NMR (MeOH-d₄, 300 MHz) δ 3.94 (m,2H), 3.98 (d, J=5.5 Hz, 1H), 4.17 (d, J=4.4 Hz, 1H), 5.30 (m, 4H), 5.60(m, 1H), 7.40 (m, 5H); MS (DCl/NH₃) m/z 266 (M+NH₄)⁺, 249 (M+H)⁺.

Example 7E benzyl(cis)-3-amino-4-(hydroxymethyl)-1-pyrrolidinecarboxylate

A solution of the product of Example 7D (240 g, 0.97 mol) in xylene (1.0L) was heated at reflux under N₂ for 10 hours. The resulting brownsolution was cooled to 10-15° C. and acetic acid (1.0 L) was added underN₂. Zinc powder (100 g, 1.54 mol) was added gradually, and the graymixture was stirred at ambient temperature for 3 hours. The mixture wasfiltered and water (1.0 L) was added to the filtrate. The filtrate wasstirred for 10 minutes and the brown organic layer was separated. Theaqueous phase was washed well with xylenes (4×400 mL) and thenconcentrated under reduced pressure to a volume of approximately 200 mL.This residue was adjusted to pH 9-10 by cautious addition of saturated,aqueous Na₂CO₃. The precipitated white solid was removed by filtrationand the filtrate was extracted with CHCl₃ (3×600 mL). The combinedorganic phases were washed with saturated, aqueous Na₂CO₃ solution (2×50mL) and dried over anhydrous Na₂CO₃. The mixture was filtered through ashort column of diatomaceous earth and the filtrate was concentratedunder reduced pressure to provide the title compound as a slightlyyellow oil (145 g, 0.58 mol, 60% yield). ¹H NMR (MeOH-d₄, 300 MHz) δ2.40 (m, 1H), 3.30 (m, 2H), 3.80-3.50 (m, 5H), 5.10 (s, 2H), 7.35 (m,5H); MS (DCl/NH₃) m/z 251 (M+H)⁺.

Example 7F Benzyl(cis)-2,2-dimethylhexahydropyrrolo[3,4-d][1,3]oxazine-6(4H)-carboxylate(R)-Mandelate

The product of Example 7E (140 g, 0.56 mol) in dry acetone (150 mL) wastreated with 2-methoxypropene (55 mL, 0.57 mol) at ambient temperaturefor ˜18 h. The reaction mixture was concentrated under reduced pressureand the residue was dissolved in dry acetone (750 mL). (R)-Mandelic acid(85 g, 0.56 mol) was added and the brown solution was stirred at ambienttemperature for 48 hours. The precipitate was isolated by filtration anddried under reduced pressure to a mixture of the title compound as awhite solid (57.0 g, 0.13 mol, yield, 23%) and the hydrolyzed compoundbenzyl (cis)-3-amino-4-(hydroxymethyl)-1-pyrrolidinecarboxylate(R)-mandelate. ¹H NMR for title compound (MeOH-D₄, 300 MHz) δ 1.20-1.40(m, 3H), 2.09 (s, 3H), 3.30 (m, 1H), 3.48-3.75 (m, 6H), 4.20 (m, 1H),5.10 (m, 3H), 7.25-7.52 (m, 10H); MS (DCl/NH₃) m/z 291 (M+H)⁺ (for thetitle compound) 251 (M+H)⁺ (for the hydrolyzed product).

Example 7G Benzyl(3S,4S)-3-[(tert-butoxycarbonyl)amino]-4-(hydroxymethyl)-1-pyrrolidinecarboxylate

The product of Example 7F (56 g, 127 mmol) in ethanol (50 mL) wastreated with 5% aqueous H₂SO₄ (100 mL) at ambient temperature andallowed to stir for 16 hours. The mixture was adjusted to pH ˜10 with20% aqueous NaOH (50 mL) and then the mixture was treated withdi-t-butyl dicarbonate (41.5 g, 190 mmol) in ethanol (50 mL) at 10-20°C. After stirring at ambient temperature for 4 hours, the ethanol wasremoved under reduced pressure and the residue was extracted with ethylacetate (3×500 mL). The combined organic phases were washed with brine(2×100 mL) and concentrated under reduced pressure to provide the titlecompound (43.7 g, 0.125 mol, 98% yield). ¹H NMR (MeOH-d₄, 300 MHz) δ1.46 (s, 9H), 2.50 (m, 1H), 3.25 (m, 1H), 3.40 (m, 1H), 3.50-3.75 (m,4H), 4.20 (m, 1H), 5.10 (s, 2H), 7.35 (m, 5H); MS (DCl/NH₃) m/z 368(M+NH₄)⁺, 351 (M+H)⁺. The enantiopurity of the title compound wasdetermined to be ≧99% ee by HPLC (HPLC conditions: Chiracel AD column;ethanol/hexanes=20/80, flow rate, 1.0 mL/min; uv 220 nm; retention timefor the title compound as the more mobile isomer: 10.8 minutes;Retention time for less mobile isomer: 13.9 minutes; reference: JP 2000026408).

Example 7H Benzyl(3S,4S)-3-[(tert-butoxycarbonyl)amino]-4-{[(methylsulfonyl)oxy]methyl}-1-pyrrolidinecarboxylate

The product of Example 7G (43.7 g, 125 mmol) and triethylamine (25.2 g,250 mmol) in CH₂Cl₂ (600 mL) were treated with methanesulfonyl chloride(12.6 mL, 163 mmol) over 30 minutes at −10° C. The solution was allowedto warm to ambient temperature over 1 hour and was monitored by HPLC.When the reaction was completed, it was quenched with water (100 mL).The layers were separated and the aqueous phase was extracted withCH₂Cl₂ (2×400 mL). The combined organic phases were washed with brine(2×100 mL), dried over Na₂SO₄, filtered and the filtrate concentratedunder reduced pressure to provide the title compound as a brown oil(52.0 g, 0.12 mol, 97% yield). ¹H NMR (CDCl₃, 300 MHz) δ 1.46 (s, 9H),2.80 (m, 1H), 3.08 (s, 3H), 3.40 (m, 2H), 3.70 (m, 2H), 4.10 (m, 1H),4.40 (m, 2H), 4.75 (m, 1H), 5.16 (s, 2H), 7.30 m, 5H); MS (DCl/NH₃) m/z446 (M+NH₄)⁺, 429 (M+H)⁺. HPLC conditions: HPLC conditions:Zorbax-XDB-C8 column 4.6×250 mm with solvents H₂O (0.2 v. % HClO₄)/MeCN(from v.80:20 to 10:90 within 15 min.) at 1.0 mL/Min., UV detection @220nm. 20/80, flow rate, 1.0 mL/min; uv 220 nm; t_(R)=13.1 minutes.

Example 7I Benzyl(3S,4S)-3-(amino)-4-{[(methylsulfonyl)oxy]methyl}-1-pyrrolidinecarboxylatetrifluoroacetate

The product of Example 7H (43.7 g, 125 mmol) in CH₂Cl₂ (150 mL) wastreated with trifluoroacetic acid (50 mL) at ambient temperature andallowed to stir for 1 h. The reaction was monitored with HPLC. After thereaction went to completion, the mixture was concentrated under reducedpressure to give the title compound in quantitative yield. ¹H NMR(CDCl₃, 300 MHz) δ 2.80 (m, 1H), 3.15 (s, 3H), 3.40 (m, 1H), 3.70 (m,3H), 4.10 (m, 1H), 4.05 (m, 1H), 4.44 (m, 2H), 5.16 (s, 2H), 7.30-7.50(m, 5H); MS (DCl/NH₃) m/z 329 (M+H−CF₃CO₂H)⁺. HPLC conditions:Zorbax-XDB-C8 column 4.6×250 mm with solvents H₂O (0.2 v. % HClO₄)/CH₃CN(from v.80:20 to 10:90 within 15 min.) at 1.0 mL/Min., UV detection @220nm. 20/80, flow rate, 1.0 mL/min; uv 220 nm; t_(R)=8.2 minutes.

Example 7J Benzyl (1S,5S)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate

The product of Example 7I (125 mmol) was dissolved in ethanol (250 mL)and adjusted to pH ˜12 with 25% aqueous NaOH. The mixture was warmed to60° C. for 1.5 h and monitored via HPLC. After the reaction went tocompletion, it was allowed to cool down to ambient temperature and usedfor the next step with the exception of ˜1 mL which was used forcharacterization. The ˜1 mL sample was concentrated under reducedpressure to remove most of the ethanol. The residue was extracted withCHCl₃ (2×5 mL). The extracts were combined, washed with brine (3×2 mL)and then passed through a short column of diatomaceous earth. Thefiltrate was concentrated under reduced pressure to provide the titlecompound as a yellow oil. ¹H NMR (MeOH-d₄, 300 MHz) δ 3.30-3.16 (m, 3H),3.36 (m, 1H), 3.82 (m, 3H), 4.55 (m, 1H), 5.20 (s, 2H), 7.36 (m, 5H); MS(DCl/NH₃) m/z 250 (M+NH₄)⁺, 233 (M+H)⁺. HPLC conditions: Zorbax-XDB-C8column 4.6×250 mm with solvents H₂O (0.2 v. % HClO₄)/MeCN (from v.80:20to 10:90 within 15 min.) at 1.0 mL/Min., UV detection @220 nm. 20/80,flow rate, 1.0 mL/min; uv 220 nm; t_(R)=7.2 min.

Example 8 tert-Butyl(1R,5S)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate Example 8A3-Benzyl,6-tert-butyl-(1R,5S)-3,6-diazabicyclo[3.2.0]heptane-3,6-dicarboxylate

To the solution of Example 7J (˜125 mmol) was slowly added di-t-butyldicarbonate (40.9 g, 188 mmol) ethanol (50 mL) solution over 30 min atambient temperature. The mixture was stirred at ambient temperature foran additional 0.5-1 h with monitoring by HPLC. After the reaction wentto completion, it was concentrated under reduced pressure to remove mostof the ethanol. The residue was extracted with EtOAc (3×500 mL). Theextracts were combined, washed with brine (3×50 mL) and stirred withKHSO₄ (5%, 100 mL) for 10 min. to remove unreacted di-t-butyldicarbonate. The layers were separated and the organic layer was washedwith brine (3×50 mL) and passed through a short column of diatomaceousearth. The filtrate was concentrated under reduced pressure to providethe title compound as a yellow oil (40.2 g, 97% three-step yield). ¹HNMR (MeOH-d₄, 300 MHz) δ 1.4 (s, 9H), 3.10 (m, 2H), 3.30 (m, 1H), 3.45(m, 1H), 3.90 (d, J=12.2 Hz, 1H), 4.06 (m, 2H), 4.66 (dd, J=6.4, 2.0 Hz,1H), 5.16 (s, 2H), 7.36 (m, 5H); MS (DCl/NH₃) m/z 333 (M+H)⁺. HPLCconditions: Zorbax-XDB-C8 column 4.6×250 mm with solvents H₂O (0.2 v. %HClO₄)/MeCN (from v.80:20 to 10:90 within 15 min.) at 1.0 mL/Min., UVdetection @220 nm. 20/80, flow rate, 1.0 mL/min; uv 220 nm; t_(R)=13.6minutes.

Example 8B tert-Butyl(1R,5S)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate

The product of Example 8A (40.0 g, 0.120 mol) was dissolved in methanol(400 mL) and treated with Pd/C (10 wt %, 4.0 g) under H₂ at ambienttemperature for 10 h. The reaction was monitored with HPLC. After thereaction was complete, the catalyst was removed by filtration through ashort column of diatomaceous earth. The filtrate was concentrated underreduced pressure to provide the title compound as a colorless oil (22.8g, 11.5 mmol, 96% yield). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.43 (s, 9H), 2.47(dd, J=12.6, 3.8 Hz, 1H), 2.62 (dd, J=12.2, 5.7 Hz, 1H), 2.96 (m, 1H),3.05 (d, J=12.2 Hz, 1H), 3.22 (d, J=12.5 Hz, 1H), 3.45 (m, 1H), 3.95 (m,1H), 4.63 (dd, J=6.1, 3.7 Hz, 1H); MS (DCl/NH₃) m/z 199 (M+H)⁺. HPLCconditions: Zorbax-XDB-C8 column 4.6×250 mm with solvents H₂O (0.2 v. %HClO₄)/MeCN (from v.80:20 to 10:90 within 15 min.) at 1.0 mL/Min., UVdetection @ 220 nm. 20/80, flow rate, 1.0 mL/min; uv 220 nm; t_(R)=8.6minutes.

Example 9 Benzyl (1R,5R)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate

The product of Example 7E was processed according to the procedure ofExample 7F, substituting (S)-mandelic acid for the (R)-mandelic acidtherein. The resulting material was processed according to theprocedures of Examples 7G, 7H, 7I, and 7J to provide the title compound:¹H NMR (MeOH-d₄, 300 MHz) δ 3.30-3.16 (m, 3H), 3.36 (m, 1H), 3.82 (m,3H), 4.55 (m, 1H), 5.20 (s, 2H), 7.36 (m, 5H); MS (DCl/NH₃) m/z 250(M+NH₄)⁺, 233 (M+H)⁺.

Example 10 tert-Butyl(1S,5R)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate

The product of Example 9 was treated with di-t-butyl dicarbonate, thenPd/C under a hydrogen atmosphere according to the procedures of Example8A and 8B, to provide the title compound. ¹H NMR (MeOH-d₄, 300 MHz) 1.43(s, 9H), 2.47 (dd, J=12.6, 3.8 Hz, 1H), 2.62 (dd, J=12.2, 5.7 Hz, 1H),2.96 (m, 1H), 3.05 (d, J=12.2 Hz, 1H), 3.22 (d, J=12.5 Hz, 1H), 3.45 (m,1H), 3.95 (m, 1H), 4.63 (dd, J=6.1, 3.7 Hz, 1H); MS (DCl/NH₃) m/z 199(M+H)⁺.

Example 11 Benzyl 2,6-diazabicyclo[3.2.1]octane-6-carboxylate Example11A Benzyl 3-oxo-2,6-diazabicyclo[3.2.1]octane-6-carboxylate

Benzyl 5-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (2.46 g, 10.0mmol), prepared according to the procedures described by (Carroll, F.I.; et. al., J. Med. Chem. (1992) 35, 2184), in 50 mL of 95% aqueousethanol at ambient temperature was treated with sodium acetate (2.47 g,30.1 mmol) and hydroxylamine hydrochloride (3.48 g, 50.1 mmol). After 45minutes, the mixture was concentrated under reduced pressure and theresidue was diluted with saturated aqueous NaHCO₃ and extracted withEtOAc. The organic extract was dried (MgSO₄) and concentrated to afford2.50 grams (96%) of a mixture of the desired oximes as a white solid. Aportion of this material (1.57 g, 6.03 mmol) was stirred in a 5:1solution of CH₂Cl₂/trimethylsilylpolyphosphate for 12 hours at ambienttemperature. The solution was diluted with H₂O and extracted twice withEtOAc. The combined organic extracts were dried (MgSO₄) and concentratedunder reduced pressure. The residue was purified by chromatography(silica gel; 95:5 CH₂Cl₂/MeOH) to provide 1.08 grams (68%) of the titlecompound as a white solid. MS (DCl/NH₃) m/z 261 (M+H)⁺, 278 (M+NH₄)⁺.

Example 11B benzyl 2,6-diazabicyclo[3.2.1]octane-6-carboxylate

The product from example 11A (800 mg, 3.07 mmol) in THF (12 mL) at 0° C.was treated dropwise with a 2.0 M solution of borane-methyl sulfidecomplex in THF (3.4 mL, 6.8 mmol). The solution was stirred for 14 hoursat ambient temperature, then recooled to 0° C. and quenched by thecareful addition of MeOH and concentrated under reduced pressure. Theresidue was dissolved in toluene (12 mL) and treated with n-propylamine(1.7 mL). The mixture was stirred for 3 hours at 60° C., allowed to coolto ambient temperature, and concentrated under reduced pressure. Theresidue was diluted with saturated aqueous NaHCO₃ and extracted withCH₂Cl₂ (4×). The organic extracts were combined, dried (K₂CO₃), andconcentrated. The residue was purified by chromatography (silica gel;90:10:1 CH₂Cl₂/MeOH/NH₄OH) to provide 453 mg (60%) of the title compoundas a colorless oil. MS (DCl/NH₃) m/z 247 (M+H)⁺.

Example 12 tert-butyl 2,6-diazabicyclo[3.2.1]octane-2-carboxylate

The product from Example 11B (140 mg, 0.568 mmol) in CH₂Cl₂ at ambienttemperature was treated with triethylamine followed by di-tert-butyldicarbonate. The solution was stirred for 2 hours, diluted withsaturated aqueous K₂CO₃, and extracted with CH₂Cl₂ (2×). The organicextracts were combined, dried (Na₂SO₄), and concentrated under reducedpressure to provide 190 mg a colorless oil. A suspension of the oil and10% Pd/C (20 mg) in MeOH (10 mL) were stirred under one atmosphere ofhydrogen (balloon) for 6 hours. The catalyst was removed by filtrationthrough a plug of Celite (CH₂Cl₂ wash). The filtrate was concentrated toprovide (106 mg, 91%) the title compound as a colorless oil. MS(DCl/NH₃) m/z 213 (M+H)⁺, 230 M+NH₄)⁺.

Example 13 9-Methyl-3,9-diazabicyclo[4.2.1]nonane

The title compound was prepared as described in U.S. Pat. No. 2,999,091.

Example 14 tert-butyl(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate Example 14Aethyl {[(1R)-1-phenylethyl]-amino}acetate

Ethyl bromoacetate (4.14 g; 24.8 mmol) was treated with (R)α-methylbenzylamine (3 g, 24.8 mmol) and ethyldiisopropylamine (3.2 g;24.8 mmol) in toluene (100 mL). After heating at reflux for 18 hours,the mixture was cooled to room temperature and concentrated underreduced pressure. The residue was purified by flash chromatography(SiO₂, 20% ethyl acetate/pentane) to provide the title compound (3.2 g,63% yield). MS (DCl/NH₃) m/z 208 (M+H)⁺.

Example 14B {[(1R)-1-phenylethyl]amino}acetic acid

The product from Example 14A (4.5 g; 15.6 mmol) in water (100 mL) washeated to reflux for 18 hours. The mixture was cooled to 30° C. andconcentrated under reduced pressure to provide the title compounds as awhite solid (2.7 g; 80% yield). MS (DCl/NH₃) m/z 180 (M+H)⁺.

Example 14C ethylcis-1-[(1R)-1-phenylethyl]hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate

The product from Example 14B (27.5 g, 154 mmol) and ethylallyl(2-oxoethyl)carbamate (26.3 g, 154 mmol), prepared as described in(U.S. Pat. No. 5,071,999), in toluene (500 mL) were heated at reflux for17 hours. The solvent was evaporated under reduced pressure to providethe crude product (45 g) as a nearly 1:1 mixture of diastereomers. Thesewere separated by flash chromatography on silica gel, eluting with 30%ethyl acetate in pentane.

The more mobile diastereomer was obtained as a thick syrup (R_(f)=0.42,pentane:ethyl acetate (3:7) 17 g, 38% yield). The stereocenters weredetermined to be (R,R) using X-Ray diffraction as described in Example14E. MS (DCl/NH₃) m/z 289 (M+H)⁺.

The less mobile diastereomer was obtained as a thick syrup (R_(f)=0.21,pentane:ethyl acetate (3:7) 17.8 g, 40% yield). The stereocenters weredetermined to be (S,S) using X-Ray diffraction as described in Example15B. MS (DCl/NH₃) m/z 289 (M+H)⁺.

Example 14D(3aR,6aR)-1-[(1R)-1-phenylethyl]octahydropyrrolo[3,4-b]pyrrole

The more mobile diastereomer from Example 14C (17 g, 59.0 mmol) inhydrochloric acid (12N, 200 mL) was heated in an oil bath at 120° C. for20 hours. The mixture was cooled to 20° C. and concentrated underreduced pressure to remove excess HCl. The residue was taken in 10%Na₂CO₃ (100 mL) and extracted with CH₂Cl₂ (3×200 mL). The organic layerswere combined, washed with brine, dried (Na₂CO₃), and concentrated. Theresidue was purified by chromatography (SiO₂, eluted withCH₂Cl₂:MeOH:NH₄OH; 90:10:1) to afford the title compound as a brownishoil (11.4 g, 89% yield). MS (DCl/NH₃) m/z 217 (M+H)⁺.

Example 14E(3aR,6aR)-5-[(4-nitrophenyl)sulfonyl]-1-[(1R)-1-phenylethyl]octahydropyrrolo[3,4-b]pyrrole

The product from Example 14D was processed as described in Example 15Bto provide the title compound. The stereocenters were determined to be(R,R) using X-ray diffraction as described in Example 15B.

Example 14F(3aR,6aR)-1-[(1R)-1-phenylethyl]-5-(trifluoroacetyl)octahydropyrrolo[3,4-b]pyrrole

The product from Example 14D (11.3 g, 52 mmol) and triethylamine (6.8 g,68 mmol) in anhydrous THF (200 mL) at 0-5° C. was treated withtrifluoroacetic anhydride (25.2 g, 63 mmol) dropwise. The reactionmixture was allowed to warm to room temperature overnight. The THF wasremoved under reduced pressure and replaced with CH₂Cl₂ (200 mL). Themethylene chloride was washed with brine, dried (MgSO₄), andconcentrated. The residue was purified using chromatography (SiO₂,eluting with 5-15% ethyl acetate/hexanes) to provide the title compoundas a light yellow oil (13.7 g, 84% yield). MS (DCl/NH₃) m/z 313 (M+H)⁺.

Example 14G tert-butyl(3aR,6aR)-5-(trifluoroacetyl)hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate

The product from Example 14F (11.2 g; 35.8 mmol) and di-tert-butyldicarbonate (8.58 g, 39.4 mmol) in methanol (400 mL) was treated with10% Pd/C (0.6 g). The mixture was shaken under an atmosphere of hydrogen(4 atm) at 25° C. for 18 hours. After filtration, the solution wasconcentrated under reduced pressure and the residue was purified bychromatography (SiO₂, 2:1 ethyl acetate:hexanes) to provide the titlecompound as a crystalline solid (9.88 g, 89% yield). MS (DCl/NH₃) m/z326 (M+NH₄)⁺.

Example 14H tert-butyl(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate

The product from Example 14G (9.88 g, 32 mmol) in methanol (200 mL) andwater (40 mL) was treated with solid potassium carbonate (4.86 g; 35mmol). After stirring at 20° C. for 18 hours, the solvent was removedunder reduced pressure. The residue was azeotroped with ethyl acetate(50 mL) twice and finally with toluene (100 mL). The dry powder wasstirred with 20% MeOH/CH₂Cl₂ (100 mL), filtered, and the filtercake wasrinsed with 20% MeOH/CH₂Cl₂ (100 mL). The filtrate was concentrated toprovide the title compound as a white solid. MS (DCl/NH₃) m/z 213(M+H)⁺.

Example 15 (tert-butyl(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate Example 15A(3aS,6aS)-1-[(1R)-1-phenylethyl]octahydropyrrolo[3,4-b]pyrrole

The less mobile diastereomer from Example 14C was processed as describedin Example 14D to provide the title compound as a brownish oil (11.3 g,76% yield). MS (DCl/NH₃) m/z 217 (M+H)⁺.

Example 15B(3aS,6aS)-5-[(4-nitrophenyl)sulfonyl]-1-[(1R)-1-phenylethyl]octahydropyrrolo[3,4-b]pyrrole

The product from Example 15A (148 mg, 0.68 mmol) and triethyl amine(0.15 mL, 1.08 mmol) in dichloromethane (5 mL) at 0° C. was treated with4-nitrobenzenesulfonyl chloride (166 mg, 0.75 mmol) in dichloromethane(2 mL) over 1 minute. The reaction mixture was allowed to warm to roomtemperature. After 1 hour, the mixture was diluted with dichloromethane(20 mL) and washed with 5% NaHCO₃ (10 mL), brine (10 mL), dried (MgSO₄)and concentrated under reduced pressure to provide the title compound asa light yellow solid (270 mg, 98%). Single crystals suitable for x-raydiffraction were grown by slow evaporation from ethyl acetate solution.Crystal data: MW=401.48, C₂₀H₂₃N₃O₄S, crystal dimensions 0.60×0.10×0.10mm, orthorhombic, P2₁2₁2₁ (#19), a=5.4031(5), b=16.168(2), c=22.687(2)Å, V=1981.8(3) Å³, Z=4, D_(calc)=1.345 g/cm⁻³. Crystallographic datawere collected using Mo K □ radiation (□=0.71069 Å). Refinement of thestructure using full matrix least squares refinement of 253 parameterson 2005 reflections with I>3.00□(I) gave R=0.117, R_(w)=0.123.

Example 15C(3aS,6aS)-1-[(1R)-1-phenylethyl]-5-(trifluoroacetyl)octahydropyrrolo[3,4-b]pyrrole

The product from Example 15A (11.3 g, 52 mmol) was processed asdescribed in Example 14F to provide the title compound (11.2 g, 69%yield). MS (DCl/NH₃) m/z 313 (M+H)⁺.

Example 15D tert-butyl(3aS,6aS)-5-(trifluoroacetyl)hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate

The product from example 15C was processed as described in Example 14Gto provide the title compound (97% yield). MS (DCl/NH₃) m/z 326(M+NH₄)⁺.

Example 15E tert-butyl(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate

The product from Example 15D was processed as described in the Example14H to provide the title compound.

Example 16 tert-butyl(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrole-5-carboxylate

The product of Example 14D was treated with di-t-butyl dicarbonate, thenhydrogenated over palladium according to U.S. Pat. No. 5,071,999(Example 3) to provide the title compound.

Example 17 tert-butyl(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrole-5-carboxylate

The product of Example 15A was processed as described in Example 16 toprovide the title compound.

Example 18 (1R,6S)-3,8-Diaza-bicyclo[4.2.0]octane-3-carboxylic acidtert-butyl ester

To the minor isomer product of Example 3E (2.4 g, 7.5 mmol) in 30 mLCH₃OH was added 0.58 g of 20% Pd(OH)₂/C (wet). This mixture was shakenunder 60 psi of H₂ for 16.5 h at 50° C. The mixture was filtered,concentrated to proved the title compound, suitable for use withoutfurther purification. MS (DCl/NH₃) m/z 213 (M+H)⁺.

Example 19 (1S,6R)-3,8-Diaza-bicyclo[4.2.0]octane-3-carboxylic acidtert-butyl ester

The major product from Example 3E was processed according to theprocedure of Example 18 to provide the title compound: MS (DCl/NH₃) m/z213 (M+H)⁺.

Example 20 6a-Methyl-octahydro-pyrrolo[3,4-b]pyrrole Example 20AN-Allyl-N-(2-hydroxypropyl)-carbamic acid benzyl ester

The product of Example 7C (13.2 g, 56.6 mmol) in THF (100 mL) wastreated with MeMgBr (3M in THF, 24.5 mL, 73.5 mmol) at −78° C. over 2hours. The mixture was then warmed to ambient temperature. The reactionwas quenched with saturated, aqueous NH₄Cl solution (50 mL) at 0° C.,the layers were separated and the aqueous layer was extracted with EtOAc(3×200 mL). The organic layers were combined and concentrated underreduced pressure. The residues were purified by column chromatography(SiO₂, 40% hexanes-ethyl acetate) to give the title compound (6.48 g, 26mmol, 46% yield). ¹H NMR (CDCl₃, 300 MHz) δ 1.16 (d, J=6.4 Hz, 3H),3.14-3.41 (m, 2H), 3.83-4.09 (m, 3H), 5.02-5.22 (m, 4H), 5.69-5.90 (m,1H), 7.20-7.40 (m, 5H); MS (DCl/NH₃) m/z 250 (M+H)⁺, 267 (M+NH₄)⁺.

Example 20B N-Allyl-N-(2-oxo-propyl)-carbamic acid benzyl ester

Dimethylsulfoxide (DMSO, 4.7 g, 60.1 mmol) was added slowly into asolution of oxalyl chloride (3.82 g, 30.1 mmol) in CH₂Cl₂ (150 ml) at−78° C. After the addition was complete, the mixture was stirred for 15minutes. The product of Example 20A (6.25 g, 25.1 mmol) in CH₂Cl₂ (20mL) was added to the above mixture at −78° C. After the mixture wasstirred for 30 minutes, triethylamine (12.6 g, 125 mmol) was added. Thereaction mixture was then warmed slowly to ambient temperature. Afterthe reaction was complete, it was quenched with water (10 mL). Thelayers were separated and the aqueous layer was extracted with EtOAc(3×200 mL). The extracts were combined and concentrated under reducedpressure. The residue was purified by column chromatography (SiO₂, 40%hexanes-ethyl acetate) to give the title compound (4.3 g, 17.4 mmol, 70%yield). ¹H NMR (CDCl₃, 300 MHz) δ 2.05 (s, 1.4H), 2.14 (s, 1.6H),3.91-4.08 (m, 4H), 5.06-5.21 (m, 4H), 5.68-5.86 (m, 1H), 7.25-7.40 (m,5H); MS (DCl/NH₃) m/z 248 (M+H)⁺, 265 (M+NH₄)⁺.

Example 20C1-Benzyl-6a-methyl-hexahydro-pyrrolo[3,4-b]pyrrole-5-carboxylic acidbenzyl ester

The product of Example 20B (3.0 g, 12.1 mmol) was treated withbenzylaminoacetic acid (Aldrich, 2.0 g, 12.1 mmol) in toluene (50 mL) at110° C. over 2 days. The toluene was removed under reduced pressure andthe residue was purified by column chromatography (SiO₂, 40%hexanes-ethyl acetate) to give the title compound (2.8 g, 8.0 mmol, 66%yield). ¹H NMR (MeOH-d₄, 300 MHz) δ 1.23 (s, 3H), 1.49-1.64 (m, 1H),1.93-2.10 (m, 1H), 2.36-2.51 (m, 1H), 2.56-2.67 (m, 1H), 2.73-2.87 (m,1H), 3.10 (d, J=11.5 Hz, 1H), 3.32-3.41 (m, 1H), 3.52 (d, J=13.2 Hz,1H), 3.58-3.78 (m, 3H), 5.03-5.22 (m, 2H), 7.14-7.42 (m, 10H); MS(DCl/NH₃) m/z 351 (M+H)⁺.

Example 20D 1-Benzyl-6a-methyl-octahydro-pyrrolo[3,4-b]pyrrole

The product of Example 20C (1.7 g, 4.85 mmol) was treated with Pd/C (10wt %, 300 mg) i-PrOH (50 mL) at ambient temperature under 1 atm of H₂for 18 h. After the reaction went completion, the catalyst was filteredoff and the filtrate was concentrated under reduced pressure to give thetitle compound (0.7 g, 3.2 mmol, 66% yield). ¹H NMR (MeOH-d₄, 300 MHz) δ1.23 (s, 3H), 1.32-1.46 (m, 1H), 1.94-2.07 (m, 1H), 2.23-2.39 (m, 2H),2.46-2.56 (m, 1H), 2.66-2.75 (m, 2H), 2.95-3.04 (m, 2H), 3.62 (d, J=12.9Hz, 1H), 3.73 (d, J=12.9 Hz, 1H), 7.13-7.37 (m, 5H); MS (DCl/NH₃) m/z217 (M+H)⁺.

Example 20E1-Benzyl-6a-methyl-hexahydro-pyrrolo[3,4-b]pyrrole-5-carboxylic acidtert-butyl ester

The product of Example 20D (700 mg, 3.24 mmol) was treated withdi-tert-butyl dicarbonate (706 mg, 3.24 mmol) and Et₃N (2 mL) in CH₂Cl₂(10 mL) for 16 hours. The mixture was then concentrated under reducedpressure and purified by column chromatography (SiO₂, 40% hexanes-ethylacetate) to give the title compound (1.02 g, 3.24 mmol, 100% yield). ¹HNMR (MeOH-d₄, 300 MHz) δ 1.22 (s, 3H), 1.47 (s, 9H), 1.49-1.62 (m, 1H),1.94-2.11 (m, 1H), 2.34-2.46 (m, 1H), 2.57-2.68 (m, 1H), 2.73-2.87 (m,1H), 3.02 (d, J=11.5 Hz, 1H), 3.21-3.27 (m, 1H), 3.50-3.74 (m, 4H),7.15-7.32 (m, 5H); MS (DCl/NH₃) m/z 317 (M+H)⁺.

Example 20F 6a-Methyl-hexahydro-pyrrolo[3,4-b]pyrrole-1,5-dicarboxylicacid 1-benzyl ester 5-tert-butyl ester

The product of Example 20E (1.02 g, 3.24 mmol) was treated with Pd/C (10wt %, 100 mg) in MeOH (50 mL) under 1 atm. H₂ at 50° C. for 16 hours.The reaction mixture was cooled to ambient temperature. The catalyst wasfiltered off and the filtrate was concentrated under reduced pressure.The residue was treated with CbzCl (0.5 mL, 3.5 mmol) and Et₃N (3 mL) inCH₂Cl₂ (20 mL) at 0° C. for 2 h. After the reaction was complete, it wasquenched with water (5 mL) and extracted with CH₂Cl₂ (3×20 mL). Theextracts were combined and concentrated under reduced pressure. Theresidue was purified by column chromatography (SiO₂, 40% hexanes-ethylacetate) to give the title compound (0.87 g, 2.42 mmol, 75% yield). ¹HNMR (MeOH-d₄, 300 MHz) δ 1.36-1.50 (m, 13H), 1.67-1.80 (m, 1H),1.98-2.14 (m, 1H), 2.53-2.68 (m, 1H), 3.14-3.32 (m, 2H), 3.49-3.68 (m,3H), 5.09 (s, 2H), 7.22-7.42 (m, 5H).

Example 20G 6a-Methyl-hexahydro-pyrrolo[3,4-b]pyrrole-1-carboxylic acidbenzyl ester

The product of Example 20F (0.8 g, 2.22 mmol) was treated with TFA (5mL) in CH₂Cl₂ (10 mL) at ambient temperature for 1 h. The mixture wasthen concentrated under reduced pressure and the residue was purified bycolumn chromatography (SiO₂, 90:9:1 CH₂Cl₂:MeOH:NH₄OH) to give the titlecompound (0.32 g, 1.23 mmol, 55% yield). ¹H NMR (MeOH-d₄, 300 MHz) δ1.42, 1.47 (s, 3H, rotamers), 1.63-1.75 (m, 1H), 1.98-2.13 (m, 1H),2.37-2.52 (m, 1H), 2.62-2.76 (m, 2H), 3.00-3.12 (m, 1H), 3.26, 3.47 (d,J=12.6 Hz, 1H, rotamers), 3.53-3.62 (m, 2H), 5.08, 5.13 (s, 2H,rotamers), 7.25-7.42 (m, 5H); MS (DCl/NH₃) m/z 261 (M+H)⁺.

Example 21 Hexahydro-pyrrolo[3,4-c]pyrrole-3a-carboxylic acid ethylester Example 21A2,5-Dibenzyl-hexahydro-pyrrolo[3,4-c]pyrrole-3a-carboxylic acid ethylester

To the ethyl propynoate (Aldrich, 3.96 g, 40 mmol) in THF (200 mL) in a3-neck, 3-L round bottom flask equipped with an addition funnel,internal thermometer, and N₂ inlet at 0° C. was added trifluoroaceticacid (TFA) (Aldrich, 0.3 mL, 4 mmol).Benzyl(methoxymethyl)trimethylsilylmethylamine (Aldrich, 23.7 g, 100mmol) in 50 mL THF was added dropwise via addition funnel over 30minutes with the reaction temperature being maintained below 5° C. Afterthe addition was complete, the mixture was allowed to warm slowly toambient temperature and then was stirred for 10 h. The mixture wasconcentrated and the residue was dissolved in 500 mL EtOAc. It waswashed with 2×50 mL saturated NaHCO₃ and 25 mL brine, dried over Na₂SO₄,and concentrated under reduced pressure. The residue was purified bycolumn chromatography (SiO₂, 50% hexanes-EtOAc) to give 14.5 g of thetitle compound (36.6 mmol, 91% yield). MS (DCl/NH₃) m/z 365 (M+H)⁺.

Example 21B Hexahydro-pyrrolo[3,4-c]pyrrole-3a-carboxylic acid ethylester

To the product of Example 21A (1.0 g, 2.75 mmol) in EtOH (10 mL) wasadded Pd(OH)₂/C (Aldrich, 20% wet, 0.20 g). This mixture washydrogenated for 2.5 h under H₂ at 50° C. The mixture was filtered andconcentrated to give the title compound (0.50 g, 2.71 mmol, 99% yield).¹H NMR (CDCl₃, 300 MHz) 1.26 (t, J=7.1 Hz, 3H), 2.67 (dd, J=11.5, 4.4Hz, 2H), 2.79 (d, J=11.9 Hz, 2H), 2.87-3.03 (m, 1H), 3.10 (dd, J=11.5,7.8 Hz, 2H), 4.17 (q, J=7.1 Hz, 2H); MS (DCl/NH₃) m/z 185 (M+H)⁺.

Example 22 Cis-3-methyl-3,8-diazabicyclo[4.3.0]nonane Example 22A2-Benzyl-hexahydro-cyclopenta[c]pyrrol-4-one

A 3-neck, 1-L round bottom flask equipped with an addition funnel,internal thermometer, and N₂ inlet at RT was charged with cyclopentenone(16.48 g, 0.20 mol) in 0.5 L of CH₂Cl₂.Benzyl(methoxymethyl)trimethylsilylmethylamine (5.0 grams, 21 mmol) andtrifluoroacetic acid (TFA) (1.07 mL, 13.9 mmol) were added. To thismixture was added additionalbenzyl(methoxymethyl)-trimethylsilylmethylamine (40 g, 0.168 mol)dropwise via addition funnel over 1 hour with the reaction temperaturebeing maintained below 25° C. (water bath). After the addition wascomplete, the mixture was stirred for 4 h. The mixture was washed with1×100 mL 10% Na₂CO₃. The layers were separated and the organic layer waswashed with 1×100 mL 23% NaCl. The organic extract was concentratedunder reduced pressure to give an oil. The oil was redissolved inmethyl-t-butyl ether (250 mL) and extracted into 1M H₃PO₄ (200 mL). Theaqueous layer was basified with 50% NaOH to pH 12. The product wasextracted with methyl-t-butyl ether (250 mL). The layers were separatedand the organic layer was washed with 23% NaCl. The layers wereseparated. The organic layer was charged with acetonitrile (50 mL) andsilica gel (10 gms). The mixture was stirred 5 minutes and filteredthrough a silica gel pad (10 grams). The filtrate was concentrated togive the title compound (35.0 grams, 81.4% of theory), which was carriedon to the next step without further purification. MS (ESI/APCI) m/z 216(M+H)⁺.

Example 22B 2-Benzyl-hexahydro-cyclopenta[c]pyrrol-4-one oxime

To the ketone from Example 22A (32.4 grams, 150 mmol) in a 1-L roundbottom flask equipped with an condenser and an N₂ inlet was added EtOH(absolute, 375 mL). To this solution was added a solution comprised ofhydroxylamine hydrochloride (13.08 g, 190 mmol) and NaOAc in water (40mL). The reaction mixture was heated at 65° C. for 1 h until TLC showedthe reaction was complete (5:1 MTBE/CH₃CN w/0.1% Et₃N; PMA char; R_(f)SM 0.75, R_(f) 0.3 and 0.4 for oxime isomers). The reaction mixture wasconcentrated in vacuo to dryness. The residue was extracted with MTBE(200 mL) and water (200 mL). The biphasic mixture was treated with 50%NaOH solution until the pH of the solution was >12. The MTBE layer waswashed with 23% NaCl solution (1×50 mL). The layers were separated andthe organic layer was concentrated in vacuo to afford 34 g of crudematerial. The residue was dissolved in MTBE (25 mL) and pentane (40 mL)and seeded with ˜10 mg of authentic seeds. The mixture was stirred andswirled occasionally for 20 minutes and filtered. The cake was washedwith 2:1 pentanes-MTBE (3×25 mL). The solid was dried in a vacuum ovento a constant weight of 11.4 grams (33%). The solid was primarily onegeometrical isomer of the oxime. MS (ESI) m/z 231 (M+H)⁺.

Example 22C 2-Benzyl-octahydro-pyrrolo[3,4-c]pyridin-4-one

A 500 mL, 3-neck, round bottom flask was charged with the syn-oxime fromExample 22B (12.0 g, 51.9 mmol) and polyphosphoric acid (120 g). Theflask was purged with N₂/vacuum 3 times. The thick mixture was heatedfor 1.25 h at 100° C. The mixture was cooled to rt and poured onto ice(240 g). The mixture was adjusted to pH=12 with 25% NaOH and extractedwith EtOAc (150 mL). The layers were separated and the aqueous layer waswashed with 1×100 mL EtOAc. The organic layers were combined and washedwith 1×50 mL of 23% aq. NaCl. The residue was concentrated in vacuo toafford 11 g of an oil. The oil was dissolved in MTBE (40 mL) and treatedwith ˜10 mg of seed crystals, followed by pentane (15 mL). The resultingslurry was stirred for 30 minutes, filtered and washed with 2:1MTBE-pentanes. The solid was dried to a constant weight of 6.4 grams. MS(CI) m/z 231 (M+H)⁺.

Example 22D 2-Benzyl-octahydro-pyrrolo[3,4-c]pyridine

To a solution of the lactam from Example 22C (0.46 g) in THF (5 mL) wasadded 1M LiAlH₄ (4.0 mL). The mixture was heated at 50° C. for 2 h,cooled to 15° C., and quenched by cautious addition of water (0.15 mL),followed by 15% NaOH (0.15 mL), then water (0.456 mL). The mixture wasstirred for 5 minutes and filtered and washed with THF (3×5 mL). Thefiltrate was concentrated in vacuo to afford 442 mg of the titlecompound as a clear oil (quantitative yield). MS (CI) m/z 217 (M+H)⁺; ¹HNMR: δ 1.8-1.5 (m, 3H), 2.33-2.10 (m, 2H), 2.8-2.4 (m, 8H), 3.75 (s,2H), 7.25 ppm (m, 5H).

Example 23 3,8-Diaza-bicyclo[3.2.1]octane-3-carboxylic acid tert-butylester Example 23A 8-Benzyl-3,8-diaza-bicyclo[3.2.1]octane-3-carboxylicacid tert-butyl ester

Di-tert-butyl dicarbonate (0.79 g, 3.6 mmol) was added to a mixture ofthe product of Example 1F (0.70 g, 3.5 mmol) in tetrahydrofuran (30 mL)and saturated, aqueous NaHCO₃ (5 mL). This mixture was stirred atambient temperature for 18 h then diluted with H₂O (10 mL) and EtOAc (15mL). The layers were separated and the aqueous layer was extracted withEtOAc (3×5 mL). The combined extract was dried over anhydrous Na₂SO₄,concentrated and purified by column chromatography (SiO₂, 50% hexanes inEtOAc) to provide the title compound (0.62 g, 59% yield). MS (DCl/NH₃)m/z 303 (M+H)⁺.

Example 23B 3,8-Diaza-bicyclo[3.2.1]octane-3-carboxylic acid tert-butylester

A solution of the product of Example 23A (0.62 g. 0.12 mmol) in EtOH (10mL) was stirred with Pd/C (Aldrich, 60 mg, 10 wt %) under 1 atmosphereof H₂ (balloon) for 18 h. The mixture was filtered, concentrated andpurified by column chromatography (SiO₂, 1% NH₄OH:9% CH₃OH:90% CH₂Cl₂)to provide the title compound (0.44 g, 100% yield). MS (DCl/NH₃) m/z 213(M+H)⁺.

Example 24 6-Benzyl-2,6-diaza-bicyclo[3.2.0]heptane Example 24A(2S,3S)-3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

3-Hydroxy-pyrrolidine-2-carboxylic acid (Aldrich, 1.31 g, 10 mmol) wastreated with di-tert-butyl dicarbanate (Aldrich, 2.18 g, 10 mmol) andNaOH (5%, 20 mL, 25 mmol) at room temperature for 2 hours. The mixturewas acidified with 5% HCl solution at 0-10° C. to bring to pH=4. Themixture was extracted with EtOAc (3×50 mL). The extracts were combinedand washed with brine (2×10 mL). The organic solution was concentratedunder vacuum to give the title compound as white solid (2.0 g, 8.6 mmol,86% yield). ¹H NMR (300 MHz, CH₃OH-d₄) δ 1.40-1.49 (m, 9H), 1.82-1.93(m, 1H), 1.97-2.12 (m, 1H), 3.46-3.60 (m, 2H), 4.07-4.18 (m, 1H), 4.38(dd, J=4.2, 1.9 Hz, 1H); MS (DCl/NH₃) m/z 232 (M+H)⁺.

Example 24B (2R,3S)-3-Hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylicacid tert-butyl ester

The product of Example 24A (2.0 g, 8.6 mmol) was treated with BH₃(Aldrich, 1M, in THF, 17 mL, 17 mmol) in THF (50 mL) at 65° C. for 1 h.The mixture was cooled and quenched with methanol (5 mL) at 0-10° C.,then concentrated under reduced pressure. The residue was treated withsaturated NaHCO₃ solution (15 mL) and stirred for additional 1 h. Theslightly yellow mixture was extracted with EtOAc (3×50 mL). The extractswere combined, washed with brine (2×10 mL), and then concentrated undervacuum to give 1.8 gram title compound as white solid (8.25 mmol, 96%yield). ¹H NMR (300 MHz, CH₃OH-d₄) δ 1.47 (s, 9H), 1.76-1.88 (m, 1H),2.03-2.19 (m, 1H), 3.33-3.58 (m, 3H), 3.59-3.71 (m, 2H), 4.30 (dd,J=15.8, 3.6 Hz, 1H); MS (DCl/NH₃) m/z 218 (M+H)⁺.

Example 24C(2R,3S)-3-Methanesulfonyloxy-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylicacid tert-butyl ester

The product of Example 24B (1.8 g, 8.25 mmol) was treated withmethanesulfonyl chloride (Aldrich, 2.37 g, 20.7 mmol) and triethylamine(3.3 g, 33.1 mmol) in methylene chloride (50 mL) at 0° C. for 4 h. Themixture was concentrated and the residue was diluted with ethyl acetate(100 mL), washed with saturated NaHCO₃ (3×10 mL) and brine (2×10 mL).The organic solution was concentrated and the residue was purified bycolumn chromatography (SiO₂, hexanes:EtOAc=40:60, v.) to provide thetitle compound (3.0 g, 8.0 mol, 97% yield). ¹H NMR (300 MHz, CH₃OH-d₄) δ1.45-1.54 (s, 9H), 2.14-2.28 (m, 1H), 2.28-2.46 (m, 1H), 3.08-3.19 (m,6H), 3.51 (dd, J=9.8, 5.8 Hz, 2H), 4.19 (s, 1H), 4.25-4.46 (m, 2H), 5.24(s, 1H); MS (DCl/NH₃) m/z 374 (M+H)⁺.

Example 24D(2R,5R)-6-Benzyl-2,6-diaza-bicyclo[3.2.0]heptane-2-carboxylic acidtert-butyl ester

The product of Example 24C (3.0 g, 8 mmol) was treated with benzyl amine(Aldrich, 2.67 g, 25 mmol) in toluene (50 mL) at 110° C. for 16 h.Toluene was removed under vacuum, and the residue was diluted withmethylene chloride (50 mL), then washed with 1N NaOH solution (2×5 mL).The organic solution was concentrated and the residue was purified bycolumn chromatography (SiO₂, hexanes/EtOAc=20/80, v.) to provide thetitle compound (1.8 g, 6.25 mol, 78% yield). ¹H NMR (300 MHz, CH₃OH-d₄)δ 1.44 (d, J=11.2 Hz, 9H), 1.52-1.65 (m, J=8.3, 3.6 Hz, 2H), 3.15-3.21(m, 2H), 3.59-3.76 (m, 4H), 3.99 (t, J=5.4 Hz, 1H), 4.16-4.28 (m, J=6.1Hz, 1H), 7.18-7.35 (m, 5H); MS (DCl/NH₃) m/z 289 (M+H)⁺.

Example 24E (2R,5R)-2,6-Diaza-bicyclo[3.2.0]heptane-2-carboxylic acidtert-butyl ester

The product of Example 24D (0.8 g, 2.78 mmol) in MeOH (50 mL) wasstirred with Pd/C (Aldrich, 5%, 120 mg) under 1 atmosphere of hydrogenat 50° C. for 2 h. The catalyst was filtered off and the filtrate wasconcentrated to give 0.46 g of the title compound (2.3 mmol, 84% yield).¹H NMR (300 MHz, CH₃OH-d₄) δ 1.45 (d, J=10.2 Hz, 9H), 1.73-1.93 (m, 2H),3.07 (dd, J=9.5, 2.4 Hz, 1H), 3.65-3.90 (m, 3H), 4.42 (s, 1H), 4.59 (t,J=5.6 Hz, 1H); MS (DCl/NH₃) m/z 199 (M+H)⁺.

Example 24F (2R,5R)-6-Benzyl-2,6-diaza-bicyclo[3.2.0]heptane

The product of Example 24D (1.0 g, 3.47 mmol) was treated withtrifluoroacetic acid (5 mL) in methylene chloride (20 mL) at ambienttemperature for 2 h. It was then concentrated, and the residue waspurified by column chromatography (SiO₂, CH₂Cl₂/MeOH/NH₄OH=90/10/1, v.)to give 0.43 g of the title compound (2.29 mol, 66% yield). ¹H NMR (300MHz, CH₃OH-d₄) δ 1.68-1.88 (m, 1H), 1.91-2.06 (m, 1H), 3.53-3.80 (m,4H), 3.96 (s, 2H), 4.34-4.46 (m, J=6.4 Hz, 2H), 7.26-7.43 (m, 5H); MS(DCl/NH₃) m/z 189 (M+H)⁺.

Example 24G (2R,5R)-2,6-Diaza-bicyclo[3.2.0]heptane-2,6-dicarboxylicacid 6-benzyl ester 2-tert-butyl ester

The product of example 24E (6.83 g, 34.5 mmol) and triethylamine (7 g,69.0 mmol) in 50 ml methylene chloride was cooled to 0° C. then treatedwith CBzCl (6.45 g, 38 mmol), the mixture was stirred at 0° C. for 3hours then concentrated under vacuum, after diluted with 50 ml EthylAcetate and washed with water (30 ml×3), the organic solution wasconcentrated and the residue was purified by column chromatography(SiO₂, hexanes/EtOAc=40/60, v.) to provide the title compound (6.25 g,18.8 mol, 55% yield). ¹H NMR (300 MHz, CD₃OD) δ 1.37-1.53 (m, 9H)1.75-1.94 (m, 1H) 2.17 (s, 1H) 3.42-3.61 (m, 2H) 3.77-3.91 (m, 1H)4.03-4.23 (m, 1H) 4.40 (s, 1H) 4.89-4.98 (m, 1H) 5.02-5.19 (m, 2H)7.17-7.45 ppm (m, 5H); MS (DCl/NH₃) m/z 333 (M+H)⁺ 350 (M+NH₄)⁺.

Example 24H (2R,5R)-2,6-Diaza-bicyclo[3.2.0]heptane-6-carboxylic acidbenzyl ester

The product of Example 24G (1.2 g, 3.61 mmol) was treated withtrifluoroacetic acid (5 mL) in methylene chloride (20 mL) at ambienttemperature for 2 h. It was then concentrated, and the residue waspurified by column chromatography (SiO₂, CH₂Cl₂/MeOH/NH₄OH=90/10/1, v.)to give 0.6 g of the title compound (2.59 mol, 72% yield). ¹H NMR (300MHz, CD₃OD) δ 1.85-2.02 (m, 1H) 2.31-2.46 (m, 1H) 3.54-3.77 (m, 2H)3.78-3.92 (m, 1H) 4.25-4.37 (m, 1H) 4.41-4.49 (m, 1H) 5.00 (t, J=4.9 Hz,1H) 5.11 (s, 2H) 7.27-7.42 ppm (m, 5H); MS (DCl/NH₃) m/z 233 (M+H)⁺.

Example 25(1R,4R)-2-(6-chloro-3-pyridinyl)-2,5-diazabicyclo[2.2.1]heptane4-methylbenzenesulfonate Example 25A tert-butyl(1R,4R)-5-benzyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

(1R,4R)-2-(benzyl)-2,5-diazabicylo[2.2.1]heptane dihydrobromide (12.4 g,35.5 mmol), prepared as described in (J. Med. Chem., (1990) 33,1344) andK₂CO₃ (16.2 g, 117 mmol) in 100 mL of DMF were treated withdi-tert-butyl dicarbonate (8.1 g, 37 mmol) at ambient temperature. Afterstirring for 16 hours, the mixture was filtered and the filtrate dilutedwith water (500 mL). The mixture was extracted with Et₂O (3×300 mL). Theextracts were combined, washed with 50% brine (10×20 mL), dried overMgSO₄, and the solvent removed under reduced pressure to provide thetitle compound (9.7 g, 94%). ¹H NMR (DMSO-d₆, 300 MHz) 61.62 (m, 1H),1.79 (d, J=9.2 Hz, 1H), 2.51 (m, 1H), 2.75 (m, 1H) 3.07 (t, J=10.2 Hz,1H), 3.32-3.41 (m, 2H), 3.67 (s, 1H), 4.16 (d, 9.8 Hz, 1H), 7.19-7.33ppm (m, 5H); MS (DCl/NH₃) m/z 199 (M+H)⁺, 216 (M+NH₄)⁺.

Example 25B tert-butyl(1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

The product from Example 25A (2 g, 6.9 mmol) in 50 mL of EtOH wastreated with 10% Pd/C (150 mg) under an H₂ atmosphere (1 atm) for 16hours. The mixture was filtered and the solvent was evaporated underreduced pressure to yield 1.28 g (93.4%) of the title compound. ¹H NMR(DMSO-d₆, MHz) δ 1.39 (s, 9H), 1.54 (d, J=5.6 Hz, 1H), 1.58 (t, J=9.5Hz, H), 2.70-2.81 (M, 2H), 3.50 (dd, J=1.02, 10.50. 1H), 3.17 (m, 1H),3.50 (s, 1H), 4.17 ppm (d, J=10.17 Hz, H); MS (DCl/NH₃) m/z 199 (M+H)⁺,216 (M+NH₄)⁺.

Examples 31-89 General Procedures for Coupling with3-Chloro-6-phenylpyridazines

Method (A): The bicyclic secondary amine (5 mmol) was combined with3-chloro-6-phenylpyridazine (Aldrich, 7.5 mmol) in toluene (50 mL).Cesium carbonate (5.5 mmol), 1,3-bis(2,6-di-1-propylphenyl)imidazoliumchloride (Strem, 0.3 mmol), tris(dibenzylideneacetone)dipalladium (0)(Pd₂(dba)₃, Strem, 0.2 mmol) were added, and the mixture was evacuated,then purged with N₂ (three times). The mixture was warmed under N₂ to85° C. for 12-72 h. The reaction was cooled to room temperature,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography to provide respective aminopyridazine.Method B: The bicyclic secondary amine (4.1 mmol),3-chloro-6-phenylpyridazine (Aldrich, 4.92 mmol) and triethylamine (1.7mL, 12.3 mmol) were combined in dry toluene (30 mL) in a sealed tube andwarmed to 110° C. for 1-5 days. The mixture was cooled to roomtemperature, diluted with CH₂Cl₂ (10 mL) and H₂O (10 mL) and the layerswere separated. The aqueous layer was extracted with CH₂Cl₂ (2×5 mL).The combined extract was dried (Na₂SO₄), concentrated under reducedpressure, and the residue was purified by column chromatography toprovide the respective aminopyridazine.Method C: The bicyclic secondary amine (95 mmol),3-chloro-6-phenylpyridazine (Aldrich, 95 mmol) andN,N-diisopropyl)ethylamine (50 mL) were combined with dimethylsulfoxide(50 mL) and the mixture was warmed to 105° C. for 24-60 h. The mixturewas cooled to room temperature, diluted with water (300 mL) andextracted with CH₂Cl₂ (2×150 mL). The combined extract was concentratedunder vacuum, and the residue purified by column chromatography toprovide the aminopyridazine.Method D: The bicyclic secondary amine (1.4 mmol),3-chloro-6-arylpyridazine (1.4 mmol) and N,N-(diisopropyl)ethylamine(0.3 mL, 1.7 mmol) were combined with 1,2-dichlorobenzene (1.5 mL). Themixture was heated in a sealed tube to 140° C. at 330 watts for 60 minin an Emry™ Creator microwave. The mixture was cooled to roomtemperature and loaded directly onto a silica column. The product waspurified by column chromatography to provide the aminopyridazine.

General Procedures for Deprotection

Method FB: The Boc-protected amine (1 mmol) was dissolved in CH₂Cl₂ (2mL) and cooled in ice as trifluoroacetic acid (1 mL) was added over 5min. The resulting solution was allowed to warm to room temperature over1 h, then concentrated under vacuum. The residue was purified by columnchromatography (eluting with MeOH-CH₂Cl₂—NH₄OH (10:90:1)) to provide thefree base.Method PD: A solution of the N-benzyl or Cbz-protected amine (1 mmol) inethanol (10 mL) was stirred with Pd/C (100 mg, 10 wt %) under hydrogen(1-4 atm) at ambient temperature for 2-4 h. The mixture was purged withnitrogen, filtered through diatomaceous earth, and concentrated to givethe free amine.

General Procedures for N-Methylation

Method EC: The Boc-protected or free amine (1 mmol) was combined with36% aqueous formalin (1-2 mmol) and 88% formic acid (1-5 mL) was added.The mixture was warmed to 100° C. for 1-2 h, then cooled to roomtemperature and concentrated under vacuum. The residue was purified bycolumn chromatography chromatography (eluting with MeOH—CH₂Cl₂—NH₄OH(10:90:1)) to provide the N-methylated free base, which was converted toa salt by one of procedures S1-S5.Method RA: The free amine (1 mmol) and NaBH(OAc)₃ (1 mmol) in 36%aqueous formalin (10-20 mL) was stirred at ambient temperature for 5-20h. The mixture was quenched with saturated, aqueous NaHCO₃ (25 mL),extracted with CH₂Cl₂ (3×25 mL), dried (Na₂SO₄) and concentrated underreduced pressure. The residue was purified by column chromatography(eluting with MeOH—CH₂Cl₂—NH₄OH (10:90:1)) to provide the N-methylatedfree base, which was converted to a salt by one of procedures S1-S5.Method MEPD: The free amine (1 mmol) and paraformaldehyde (1.1 mmol) inethanol (10 mL) was stirred with Pd/C (100 mg, 10 wt %) under hydrogen(1-4 atm) at ambient temperature for 2-4 h. The mixture was purged withnitrogen, filtered through diatomaceous earth, and concentrated to givethe free amine. The residue was purified by column chromatography(eluting with MeOH—CH₂Cl₂—NH₄OH (10:90:1)) to provide the N-methylatedfree base, which was converted to a salt by one of procedures S1-S5,below.

General Methods for Salt Formation

Methods S1-S5: The base was combined with 1-2 equivalents of one of thefollowing acids in the solvent indicated, and the resulting precipitatewas isolated by filtration and dried to provide the named salt:

-   -   Method S1: 4-methylbenzenesulfonic acid (EtOH-EtOAc)    -   Method S2: fumaric acid (10% MeOH-ether)    -   Method S3: HCl (EtOH-EtOAc)    -   Method S4: Trifluoroacetic acid (10% MeOH-ether)    -   Method S5: L-tartaric acid (MeOH-EtOAc)

Starting Example Material Conditions Resulting Compound 31 Example 1I 1)A 3-(6-Phenyl-pyridazin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane 2) FBbis-p-toluenesulfonate 3) S1 ¹H NMR (MeOH-d₄, 300 MHz) δ 2.15 (m, 4H),2.35 (s, 6H), 3.53 (m, 1H), 3.58 (m, 1H), 4.32 (m, 3H), 4.37 (m, 1H),7.22 (m, 4H), 7.64 (m, 3H), 7.68 (m, 4H), 7.93 (m, 2H), 7.97 (d, J = 9.8Hz, 1H), 8.36 (d, J = 9.3 Hz, 1H); MS (DCI/NH₃) m/z 267; Anal.C₁₆H₁₈N₄•2C₇H₈O₃S: C, H, N 32 Example 3I 1) A3-(6-Phenyl-pyridazin-3-yl)-3,8-diaza-bicyclo[4.2.0]octane 2) FBbis(trifluoroacetate) 3) S4 ¹H NMR (CH₃OH-d₄, 300 MHz) δ 2.10 (dq, J =15.3, 4.1 Hz, 1H), 2.31 (m, 1H), 3.27 (m, 1H), 3.72 (ddd, J = 12.2, 5.4,3.7 Hz, 1H), 3.83 (dd, J = 15.3, 3.4 Hz, 1H), 4.05 (m, 2H), 4.22 (dd, J= 11.2, 9.2 Hz, 1H), 4.61 (dd, J = 15.3, 3.1 Hz, 1H), 4.90 (m, 1H), 7.54(m, 3H), 7.63 (d, J = 9.8 Hz, 1H), 7.95 (m, 2H), 8.16 (d, J = 9.8 Hz,1H); MS (DCI/NH₃) m/z 267 (M + H)⁺; Anal. calculated forC₁₆H₁₈N₄•2CF₃CO₂H: C, 48.59; H, 4.08; N, 11.33. Found: C, 48.69; H,4.34; N, 11.04. 33 Example 3I 1) B3-(6-Phenyl-pyridazin-3-yl)-3,8-diaza-bicyclo[4.2.0]octane 2) FBbis-trifluoroacetate 3) S4 ¹H NMR (300 MHz, CD₃OD) δ 2.10 (m, 1H), 2.31(m, 1H), 3.24 (m, 1H), 3.73 (dt, J = 12.6, 5.7, 4.1 Hz, 1H), 3.83 (dd, J= 15.3, 3.4 Hz, 1H), 4.05 (m, 2H), 4.23 (dd, J = 11.2, 9.2 Hz, 1H), 4.61(dd, J = 15.3, 3.1 Hz, 1H), 4.91 (dt, J = 9.3, 3.2, 3.1 Hz, 1H), 7.55(m, 3H), 7.64 (d, J = 9.8 Hz, 1H), 7.95 (m, 2H), 8.19 ppm (d, J = 9.5Hz, 1H); MS (DCI/NH₃) m/z 267 (M + H)⁺; Anal. calculated forC₁₆H₁₈N₄•2CF₃CO₂H: C, 48.59; H, 4.08; N, 11.33. Found: C, 48.15; H,4.16; N, 11.07. 34 Example 18 1) B8-(6-Phenyl-pyridazin-3-yl)-3,8-diaza-bicyclo[4.2.0]octane 2) FBp-toluenesulfonate 3) S1 ¹H NMR (300 MHz, CD₃OD) δ 2.09 (m, 1H), 2.34(s, 3H), 2.39 (m, 2H), 2.99 (m, 1H), 3.22 (m, 1H), 3.41 (dd, J = 14.4,3.2 Hz, 1H), 3.59 (m, 1H), 3.92 (m, 2H), 4.19 (t, J = 7.6 Hz, 1H), 4.78(m, 1H), 7.21 (m, 3H), 7.51 (m, 3H), 7.68 (m, 2H), 7.92 (m, 2H), 8.04ppm (d, J = 9.5 Hz, 1H); MS (DCI/NH₃) m/z 267 (M + H)⁺; Anal. calculatedfor C₁₆H₁₈N₄•1.35C₇H₈O₃S: C, 61.28; H, 5.82; N, 11.23. Found: C, 61.08;H, 5.88; N, 11.37. 35 Example 23B 1) B3-Methyl-8-(6-phenyl-pyridazin-3-yl)-3,8-diaza- 2) FBbicyclo[3.2.1]octane bis p-toluenesulfonate 3) S1 ¹H NMR (300 MHz,CD3OD) δ 2.20 (m, 2H), 2.36 (s, 6H), 2.40 (m, 2H), 2.91 (s, 3H), 3.27(m, 1H), 3.43 (m, 1H), 3.43 (m, 1H), 3.64 (br d, J = 11.9 Hz, 1H), 5.02(m, 2H), 7.22 (m, 4H), 7.62 (m, 3H), 7.69 (m, 4H), 7.94 (m, 2H), 8.03(d, J = 9.8 Hz, 1H), 8.43 ppm (d, J = 9.8 Hz, 1H); MS (DCI/NH3) m/z 281(M + H)+; Anal. calculated for C17H20N4•2.3C7H8O3S•0.6H2O: C, 57.85; H,5.81; N, 8.15. Found: C, 57.58; H, 5.83; N, 8.46. 36 Example 6C 1) C2-(6-Phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole 2) FBtrifluoroacetate 3) S4 ¹H NMR (CH₃OH-d₄, 300 MHz) δ 3.36 (m, 4H), 3.65(m, 2H), 3.75 (dd, J = 11.5, 3.1 Hz, 2H), 3.89 (m, 2H), 7.46 (d, J = 9.5Hz, 1H), 7.53 (m, 3H), 7.96 (m, 2H), 8.17 (d, J = 9.8 Hz, 1H); MS(DCI/NH₃) m/z 267 (M + H)⁺; Anal. calculated for C₁₆H₁₈N₄•1.7CF₃CO₂H: C,50.63; H, 4.31; N, 12.17. Found: C, 50.50; H, 4.14; N, 12.14. 37 Example20D 1) A 6a-Methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro- 2) PDpyrrolo[3,4-b]pyrrole fumarate 3) S2 ¹H NMR (CH₃OH-d₄, 300 MHz) δ ppm1.66 (s, 3H), 2.02-2.15 (m, 1H), 2.40-2.54 (m, 1H), 2.88-2.98 (m, 1H),3.42-3.49 (m, 2H), 3.59-3.70 (m, 2H), 3.82 (dd, J = 10.9, 8.1 Hz, 1H),4.20 (d, J = 12.5 Hz, 1H), 6.68 (s, 2H), 7.15 (d, J = 9.5 Hz, 1H),7.39-7.53 (m, 3H), 7.90-7.97 (m, 3H); MS (DCI/NH₃) m/z 281 (M + H)⁺.Anal. C₁₇H₂₀N₄•C₄H₄O₄: C, H, N. 38 Example 7J 1) A(1S,5S)-6-(6-Phenyl-pyridazin-3-yl)-3,6-diaza- 2) FBbicyclo[3.2.0]heptane fumarate 3) S2 ¹H NMR (MeOH-d₄, 300 MHz) δ 3.25(dd, J = 13.2, 4.0 Hz, 1H), 2.38 (dd, J = 12.2, 7.0 Hz, 1H), 3.50 (m,1H), 3.74 (d, J = 12.3 Hz, 1H), 3.87 (d, J = 12.9 Hz, 1H), 3.90 (dd, J =8.6, 3.4 Hz, 1H), 4.29 (t, J = 8.3 Hz, 1H), 5.21 (dd, J = 6.4, 3.6 Hz,1H), 6.67 (s, 2H), 6.99 (d, J = 9.5 Hz, 1H), 7.38-7.52 (m, 3H),7.90-7.99 (m, 3H); MS (DCI/NH₃) m/z 253 (M + H)⁺; Anal. calculated forC₁₅H₁₆N₄•C₄H₄O₄•0.3H₂O: C, 61.05; H, 5.55; N, 14.99. Found: C, 61.27; H,5.55; N, 14.63. 39 Example 8B 1) A(1R,5S)-3-(6-Phenyl-pyridazin-3-yl)-3,6-diaza- 2) FBbicyclo[3.2.0]heptane bis-p-toluenesulfonate 3) S1 ¹H NMR (MeOH-d₄, 300MHz) δ 2.24 (s, 6H), 3.70 (m, 2H), 3.81 (dd, J = 13.9, 5.7 Hz, 1H), 3.88(dd, J = 13.2, 4.0 Hz, 1H), 4.32 (m, 2H), 4.60 (d, J = 13.9 Hz, 1H),5.22 (m, 1H), 7.19 (d, J = 7.8 Hz, 4H), 7.62 (m, 3H), 7.67 (d, J = 8.2Hz, 4H), 7.90-8.02 (J = m, 3H), 8.40 (d, J = 9.5 Hz, 1H).; MS (DCI/NH₃)m/z 253 (M + H)⁺. Anal. Calculated for C₁₅H₁₆N₄•2.00C₇H₈SO₃: C, 58.37;H, 5.41; N, 9.39. Found: C, 58.27; H, 5.29; N, 9.21. 40 Example 10 1) A(1S,5R3-(6-Phenyl-pyridazin-3-yl)-3,6-diaza- 2) FB bicyclo[3.2.0]heptanebis-p-toluenesulfonate 3) S1 ¹H NMR (MeOH-d₄, 300 MHz) δ 2.23 (s, 3H),3.34 (m, 1H), 3.70 (m, 1H), 3.81 (dd, J = 13.9, 3.8 Hz, 1H), 3.86 (m,1H), 4.32 (m, 2H), 4.58 (d, J = 13.6 Hz, 1H), 5.22 (m, 1H), 7.20 (d, J =8.1 Hz, 2H), 7.62 (m, 3H), 7.67 (d, J = 8.5 Hz, 2H), 7.80 (m, 3H), 8.42(d, J = 9.9 Hz, 1H); MS (DCI/NH₃) m/z 253 (M + H)⁺. Anal. Calculated forC₁₅H₁₆N₄•2.00C₇H₈SO₃•1.00H₂O: C, 56.66; H, 5.57; N, 9.11. Found: C,56.59; H, 5.25; N, 8.80. 41 Example 25B 1)B2-(6-Phenyl-pyridazin-3-yl)-2,5-diaza-bicyclo[2.2.1]heptane 2) FBp-toluenesulfonate 3) S1 ¹H NMR (300 MHz, D₂O) d ppm 2.11-2.26 (m, 1H)2.40 (s, 3H) 2.30-2.33 (m, 1H) 3.52 (s, 2H) 3.65-3.80 (m, 1H) 3.80-3.99(m, 1H) 4.60-4.75 (m, 2H) 7.24 (d, J = 9 Hz, 1H) 7.37 (d, J = 8 Hz, 2H)7.53-7.64 (m, 3H) 7.69 (d, J = 8 Hz, 2H) 7.82-8.00 (m, 3H); MS (DCI/NH₃)m/z 257 (M + H)⁺. Anal. Calculated for C15H16N4•1.1C₇H₈SO₃ Ca, 61.53, H5.66, N12.68. Found C, 61.53, H, 5.50, N, 12.82 42 Example 21B 1) A2-(6-Phenyl-pyridazin-3-yl)-hexahydro-pyrrolo[3,4- 2) S3c]pyrrole-3a-carboxylic acid ethyl ester trihydrochloride ¹H NMR(MeOH-d₄, 300 MHz) δ 1.34 (t, J = 7.1 Hz, 3H), 3.46-3.72 (m, 4H), 3.78(dd, J = 11.7, 7.0 Hz, 1H), 3.93 (dd, J = 11.7, 4.6 Hz, 1H), 4.02-4.20(m, 2H), 4.24-4.45 (m, 3H), 7.40-7.75 (m, 3H), 7.43-7.74 (m, 3H), 7.86(d, J = 9.8 Hz, 1H), 7.91-8.14 (m, 2H), 8.47 (d, J = 9.8 Hz, 1H), 8.46(d, 1H); MS (DCI/NH₃) m/z 339 (M + H)⁺. Anal. Calculated forC₁₉H₂₂N₄O₂•3.00HCl•1.00H₂O: C, 48.99; H, 5.84; N, 12.03. Found: C,49.12; H, 5.45; N, 12.43. 43 Example 21B 1) A2,5-Bis-(6-phenyl-pyridazin-3-yl)-hexahydro-pyrrolo[3,4- 2) S3c]pyrrole-3a-carboxylic acid ethyl ester bishydrochloride ¹H NMR(MeOH-d₄, 300 MHz) δ 1.33 (t, J = 7.1 Hz, 1H), 3.67-3.84 (m, 1H),3.86-4.03 (m, 2H), 4.10 (q, J = 7.1 Hz, 5H), 4.33 (q, J = 7.1 Hz, 2H),4.44 (d, J = 11.9 Hz, 1H), 7.45-7.71 (m, 6H), 7.86 (d, J = 9.8 Hz, 2H),7.90-8.12 (m, 4H), 8.47 (d, J = 9.8 Hz, 2H); MS (DCI/NH3) m/z 493 (M +H)+. Anal. Calculated for C29H28N6O2•2.45HCl•1.6C4H8O2: C, 58.82; H,6.03; N, 11.63. Found: C, 59.12; H, 5.65; N, 11.35. 44 Example 24E 1) A(1R,5R)-6-(6-Phenyl-pyridazin-3-yl)-2,6-diaza- 2) FBbicyclo[3.2.0]heptane Bisfumarate 3) S2 ¹H NMR (300 MHz, CH₃OH-d₄) δ1.98-2.14 (m, 1H), 2.55 (dd, J = 14.2, 5.4 Hz, 1H), 3.69-3.84 (m, 2H),4.11 (dd, J = 10.3, 2.9 Hz, 1H), 4.47 (dd, J = 10.5, 7.1 Hz, 1H),4.60-4.67 (m, 1H), 5.22 (t, J = 5.1 Hz, 1H), 6.75 (s, 4H), 7.05 (d, J =9.2 Hz, 1H), 7.42-7.54 (m, 3H), 7.90-7.97 (m, 3H); MS (DCI/NH₃) m/z 253(M + H)⁺; Anal. C₁₅H₁₆N₄•2C₄H₄O₄•1.2C₂F₃HO₂: C, H, N. 45 Example 24F 1)A (1R,5R)-2-(6-Phenyl-pyridazin-3-yl)-2,6-diaza- 2) PDbicyclo[3.2.0]heptane fumarate 3) S2 ¹H NMR (300 MHz, CH₃OH-d₄) δ2.38-2.58 (m, 2H), 3.64 (dd, J = 11.4, 3.2 Hz, 1H), 3.81-3.94 (m, 1H),4.15-4.26 (m, 1H), 4.39 (dd, J = 11.4, 5.9 Hz, 1H), 5.05 (dt, J = 5.9,3.1 Hz, 1H), 5.22 (t, J = 6.1 Hz, 1H), 6.68 (s, 2H), 7.25 (d, J = 9.5Hz, 1H), 7.40-7.53 (m, 3H), 7.89-8.01 (m, 3H); MS (DCI/NH₃) m/z 253 (M +H)⁺; Anal. C₁₅H₁₆N₄•1.2C₄H₄O₄: C, H, N. 46 Example 25B 1) B2-Methyl-5-(6-phenyl-pyridazin-3-yl)-2,5-diaza- 2) FBbicyclo[2.2.1]heptane p-toluenesulfonate 3) MEPD ¹H NMR MeOH-d₄, (300MHz) d ppm 2.34 (s, 3H) 2.36-2.42 (m, 1H) 4) S1 2.39-2.61 (m, 1H) 3.02(s, 3H) 3.86 (s, 4H) 4.50 (s, 1H) 5.12 (s, 1H) 7.20 (dd, J = 9, 4 Hz,3H) 7.34-7.60 (m, 3H) 7.68 (d, J = 8 Hz, 2H) 7.85-8.04 (m, 3H), MS(DCI/NH₃) m/z 267 (M + H)⁺; Anal. Calculated for C₁₆H₁₈N₄•1.1C₇H₈SO₃ C,62.73,, 5.51, N.12.35. Found C, 62.81, H, 5.90, N, 12.46. 47 Example21B 1) A Ethyl 2-Methyl-5-(6-phenyl-pyridazin-3-yl)-hexahydro- 2) RApyrrolo[3,4-c]pyrrole-3a-carboxylate dihydrochloride 3) S3 ¹H NMR(MeOH-d₄, 300 MHz) δ 1.34 (t, J = 7.1 Hz, 3H), 3.05 (s, 3H), 3.22-3.45(m, 4H), 3.96-4.25 (m, 5H), 4.33 (q, J = 7.1 Hz, 2H) 7.52-7.67 (m, 3H)7.84 (d, J = 9.8 Hz, 1H) 7.91-8.07 (m, 2H) 8.45 (d, J = 9.8 Hz, 1H); MS(DCI/NH₃) m/z 353 (M + H)⁺; Anal. calculated for C₂₀H₂₄N₄O₂•2.00HCl•1.7H₂O•0.20C₄H₉O₂: C, 57.73; H, 6.42; N, 13.46. Found: C,58.86; H, 5.21; N, 12.25. 48 Example 22 1) RA5-Methyl-2-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4- 2) PDc]pyridine trifluoroacetate 3) D ¹H NMR (MeOH-d₄, 300 MHz) δ 1.87-2.26(m, 2H) 2.67-2.78 (m, J = 4.7 Hz, 4) S4 1H) 2.80-2.88 (m, J = 5.4 Hz,1H) 2.90 (s, 3H) 3.22-3.29 (m, J = 5.1 Hz, 2H) 3.37-3.49 (m, J = 12.4,4.6 Hz, 2H) 3.55-3.65 (m, 2H) 3.74 (dd, J = 10.5, 7.8 Hz, 2H) 7.06 (d, J= 9.5 Hz, 1H) 7.37-7.53 (m, 3H) 7.89 (d, J = 9.8 Hz, 1H) 7.89-7.96 (m,2H); MS (DCI/NH₃) m/z 295; Anal. C₁₈H₂₂N₄•C₂HF₃O₂: C, H, N 49 Example25B 1) B 2-Benzyl-5-(6-phenyl-pyridazin-3-yl)-2,5-diaza- 2) FBbicyclo[2.2.1]heptane p-toluenesulfonate 3) S1 1H NMR (300 MHz,DEUTERIUM OXIDE) d ppm 2.40 (s, 3H) 2.41-2.59 (m, 1H) 3.60 (s, 2H) 3.88(s, 1H) 4.15 (q, J = 7 Hz, 1H) 4.37-4.83 (m, 5H) 7.22 (d, J = 9 Hz, 1H)7.37 (d, J = 8 Hz, 2H) 7.47-7.65 (m, 8H) 7.69 (d, J = 8 Hz, 2H)7.81-7.99 (m, 3H)); MS (DCI/NH₃) m/z 343 (M + H)⁺; Anal. calculated forC₂₂H₂₂ N₄O₂•C₇H₈O₃S: C, 67.68; H, 5.86; N, 10.89. Found: C, 67.43; H,5.73; N, 10.72. 50 Example 20D 1) A1-Benzyl-6a-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro- 2) S2pyrrolo[3,4-b]pyrrole difumarate ¹H NMR (MeOH-d₄, 300 MHz) δ ppm1.42-1.52 (m, 3H), 1.64-1.77 (m, 1H), 1.99-2.22 (m, 2H), 2.58-2.79 (m,2H), 2.81-2.92 (m, 1H), 3.49-3.57 (m, 1H), 3.64-3.96 (m, 4H), 7.04 (d, J= 9.5 Hz, 1H), 7.14-7.52 (m, 9H), 7.84 (d, J = 9.8 Hz, 1H), 7.89-7.97(m, 1H); MS (DCI/NH₃) m/z 371 (M + H)⁺; Anal. C₂₄H₂₆N₄•2C₄H₄O₄•0.2H₂O:C, H, N. 51 Example 6C 1) C2-Methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4- 2) FBc]pyrrole dihydrochloride 3) EC ¹H NMR (CH₃OH-d₄, 300 MHz) δ 2.96 and3.03 (rotamer s, 3H), 3.16 (m, 4) S3 1H), 3.47 (m, 2H), 3.60 (m, 1H),3.77 (m, 1H), 3.93 (m, 3H), 4.01 (m, 2H), 7.58 (m, 3H), 7.79 and 7.81(rotamer d, J = 9.4 Hz, 1H), 7.95 (m, 2H), 8.41 and 8.42 (rotamer d, J =9.4 Hz, 1H); MS (DCI/NH₃) m/z 281 (M + H)⁺; Anal. calculated forC₁₇H₂₀N₄•2HCl•1.5H₂O: C, 53.69; H, 6.63; N, 14.73. Found: C, 53.59; H,6.72; N, 14.96. 52 Example 2D 1) B6-Methyl-3-(6-phenyl-pyridazin-3-yl)-3,6-diaza- 2) FBbicyclo[3.2.1]octane p-toluenesulfonate 3) EC ¹H NMR (MeOH-d₄, 300 MHz)δ 2.15 (m, 1H), 2.34 (s, 3H), 2.48 (m, 1H), 4) S1 2.95 (s, 3H), 3.22 (m,3H), 3.31 (m, 1H), 3.80 (m, 1H), 4.12 (m, 2H), 4.60 (m, 1H), 7.21 (m,2H), 7.39 (d, J = 9.5 Hz, 1H), 7.50 (m, 3H), 7.69 (m, 2H), 7.94 (m, 2H),7.95 (d, J = 9.5 Hz, 1H). MS (DCI/NH₃) m/z 281 (M + H)⁺; Anal.C₁₇H₂₀N₄•C₇H₈O₃S: C, H, N. 53 Example 5B 1) B3-Methyl-6-(6-phenyl-pyridazin-3-yl)-3,6-diaza- 2) ECbicyclo[3.2.1]octane p-toluenesulfonate 3) S1 ¹H NMR (300 MHz, CD₃OD) δppm 2.16 (m, 2H), 2.34 (s, 3H), 2.88 (s, 3H), 2.94 (m, 1H), 3.24 (m,2H), 3.41 (m, 1H), 3.64 (m, 2H), 3.78 (m, 2H), 7.21 (m, 3H), 7.49 (m,3H), 7.67 (m, 2H), 7.92 (m, 2H), 7.98 (m, 1H); MS (DCI/NH₃) m/z 281 (M +H)⁺; Anal. calculated for C₁₇H₂₀N₄•C₇H₈O₃S: C, 63.69; H, 6.24; N, 12.38.Found: C, 64.10; H, 5.96; N, 11.81. 54 Example 4 1) B8-(6-Phenyl-pyridazin-3-yl)-3,8-diaza-bicyclo[4.2.0]octane 2) FBp-toluenesulfonate 3) EC ¹H NMR (300 MHz, CD₃OD) δ 2.10 (m, 1H), 2.35(m, 1H), 2.36 (s, 3H), 4) S1 2.93 (m, 1H), 3.20 (m, 2H), 3.39 (dd, J =14.2, 3.1 Hz, 1H), 3.56 (m, 1H), 3.88 (dd, J = 7.8, 2.7 Hz, 1H), 3.93(dd, J = 14.6, 2.0 Hz, 1H), 4.14 (t, J = 7.5 Hz, 1H), 4.73 (dt, J = 5.2,2.5 Hz, 1H), 7.10 (d, J = 9.2 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.49(m, 3H), 7.70 (d, J = 8.1 Hz, 2H), 7.92 (m, 2H), 7.97 ppm (d, J = 9.2Hz, 1H); MS (DCI/NH₃) m/z 267 (M + H)⁺; Anal. calculated forC₁₆H₁₈N₄•C₇H₈O₃S•0.25H₂O: C, 62.35; H, 6.03; N, 12.65. Found: C, 62.19;H, 6.00; N, 12.30. 55 Example 3I 1) B8-Methyl-3-(6-phenyl-pyridazin-3-yl)-3,8-diaza- 2) ECbicyclo[4.2.0]octane p-toluenesulfonate 3) S1 ¹H NMR (CH₃OH-d₄, 300 MHz)δ 2.15 (dq, J = 14.9, 4.8 Hz, 1H), 2.29 (s, 6H), 2.35 (m, 1H), 3.02 (m,3H), 3.26 (m, 1H), 3.72 (dt, J = 12.9, 4.8 Hz, 1H), 3.84 (dd, J = 15.3,3.1 Hz, 1H), 4.14 (m, 2H), 4.32 (dd, J = 11.2, 4.8 Hz, 1H), 4.59 (dd, J= 15.6, 2.4 Hz, 1H), 4.79 (dt, J = 9.5, 2.7 Hz, 1H), 7.16 (m, 4H), 7.61(m, 3H), 7.63 (m, 4H), 7.92 (m, 2H), 7.93 (d, J = 9.8 Hz, 1H), 8.28 (d,J = 10.0 Hz, 1H); MS (DCI/NH₃) m/z 281 (M + H)⁺; Anal. calculated forC₁₇H₂₀N₄•2C₇H₈O₃S•H₂O: C, 57.93; H, 5.96; N, 8.72. Found: C, 57.84; H,5.75; N, 8.62. 56 Example 19 1) B3-Methyl-8-(6-phenyl-pyridazin-3-yl)-3,8-diaza- 2) FBbicyclo[4.2.0]octane L-tartrate ¹H NMR (300 MHz, CD₃OD) δ 3) S5 2.22 (m,1H), 2.49 (m, 1H), 2.81 (m, 1H), 2.89 (s, 3H), 3.02 (ddd, J = 12.0, 3.9Hz, 1H), 3.26 (m, 1H), 3.54 (m, 1H), 3.75 (dd, J = 7.3, 1.9 Hz, 1H),4.07 (m, 2H), 4.39 (s, 2H), 4.69 (m, 1H), 7.07 (d, J = 9.2 Hz, 1H), 7.48(m, 3H), 7.92 (m, 2H), 7.94 ppm (d, J = 9.2 Hz, 1H); MS (DCI/NH₃) m/z281 (M + H)⁺; Anal. calculated for C₁₇H₂₀N₄•C₄H₆O₆: C, 58.59; H, 6.09;N, 13.02. Found: C, 58.24; H, 5.97; N, 12.74. 57 Example 18 1)3-Methyl-8-(6-phenyl-pyridazin-3-yl)-3,8-diaza- 2) bicyclo[4.2.0]octaneL-tartrate ¹H NMR (300 MHz, CD₃OD) δ 3) 2.22 (m, 1H), 2.50 (m, 1H), 2.80(m, 1H), 2.88 (s, 3H), 3.00 (m, 1H), 3.24 (dd, J = 13.9, 3.4 Hz, 1H),3.55 (m, 1H), 3.75 (dd, J = 7.3, 1.9 Hz, 1H), 4.07 (m, 2H), 4.39 (s,2H), 4.68 (m, 1H), 7.07 (d, J = 9.5 Hz, 1H), 7.49 (m, 3H), 7.92 (m, 2H),7.94 ppm (d, J = 9.2 Hz, 1H); MS (DCI/NH₃) m/z 281 (M + H)⁺; Anal.calculated for C₁₇H₂₀N₄•1.2C₄H₆O₆•1 H₂O: C, 54.32; H, 6.15; N, 11.71.Found: C, 54.94; H, 6.54; N, 11.37. 58 Example 23B 1)3-Methyl-8-(6-phenyl-pyridazin-3-yl)-3,8-diaza- 2) bicyclo[3.2.1]octanebis p-toluenesulfonate 3) ¹H NMR (300 MHz, CD₃OD) δ 2.20 (m, 2H), 2.36(s, 6H), 2.40 (m, 2H), 2.91 (s, 3H), 3.27 (m, 1H), 3.43 (m, 1H), 3.43(m, 1H), 3.64 (br d, J = 11.9 Hz, 1H), 5.02 (m, 2H), 7.22 (m, 4H), 7.62(m, 3H), 7.69 (m, 4H), 7.94 (m, 2H), 8.03 (d, J = 9.8 Hz, 1H), 8.43 ppm(d, J = 9.8 Hz, 1H); MS (DCI/NH₃) m/z 281 (M + H)⁺; Anal. calculated forC₁₇H₂₀N₄•2.3C₇H₈O₃S•6H₂O: C, 57.85; H, 5.81; N, 8.15. Found: C, 57.58;H, 5.83; N, 8.46. 59 Example 8 1) A(1S,5S)-6-Methyl-3-(6-phenyl-pyridazin-3-yl)-3,6-diaza- 2) FBbicyclo[3.2.0]heptane fumarate 3) RA ¹H NMR (MeOH-d₄, 300 MHz) δ 2.88(s, 3H), 3.37-3.60 (m, 3H), 3.89 (dd, 4) S2 J = 11.2, 4.7 Hz, 1H),4.00-4.15 (m, 2H), 4.48 (d, J = 13.6 Hz, 1H), 4.90 (m, 1H), 6.69 (s,2.4H), 7.32 (d, J = 9.5 Hz, 1H), 7.39-7.53 (m, 3H), 7.90-8.02 (m, 3H).;MS (DCI/NH₃) m/z 267 (M + H)⁺; Anal. C₁₆H₁₈N₄•1.2C₄H₄O₄•0.5H₂O: C, H, N.60 Example 10 1) A(1R,5S)-6-Methyl-3-(6-phenyl-pyridazin-3-yl)-3,6-diaza- 2) FBbicyclo[3.2.0]heptane bis-p-toluenesulfonate 3) RA ¹H NMR (MeOH-d₄, 300MHz) δ 2.31 (s, 3H) 2.94-3.11 (m, 3H), 4) S1 3.45-3.77 (m, 2H),4.06-4.36 (m, 2H), 4.60 (d, J = 13.6 Hz, 1H), 4.94-5.13 (m, 1H), 7.18(d, J = 8.1 Hz, 2H), 7.44-7.54 (m, 3H), 7.60 (d, J = 9.5 Hz, 1H), 7.66(d, J = 8.1 Hz, 1H), 8.15 (d, J = 9.5 Hz, 1H); MS (DCI/NH₃) m/z 267 (M +H)⁺; Anal. Calculated for C₁₆H₁₈N₄•1.34C₇H₈SO₃•0.5H₂O: C, 60.23; H,5.92; N, 11.07. Found: C, 60.32; H, 5.72; N, 10.67. 61 Example 7 1) A(1R,5S)-3-Methyl-6-(6-phenyl-pyridazin-3-yl)-3,6-diaza- 2) FBbicyclo[3.2.0]heptane fumarate 3) RA ¹H NMR (MeOH-d₄, 300 MHz) δ 3.00(s, 3H), 3.12 (dd, J = 12.2, 3.7 Hz, 4) S2 1H), 3.20 (dd, J = 12.2, 7.5Hz, 1H), 3.50 (m, 1H), 3.89 (d, J = 12.2 Hz, 1H), 3.93 (dd, J = 8.4, 3.4Hz, 1H), 4.01 (d, J = 12.2 Hz, 1H), 4.29 (t, J = 8.2 Hz, 1H), 5.21 (dd,J = 7.1, 3.7 Hz, 1H), 6.69 (s, 3H), 7.01 (d, J = 9.2 Hz, 1H), 7.38-7.52(m, 3H), 7.90-7.99 (m, 3H).; MS (DCI/NH₃) m/z 267 (M + H)⁺; Anal.calculated for C₁₆H₁₈N₄•1.5C₄H₄O₄•0.5H₂O: C, 58.79; H, 5.61; N, 12.47.Found: C, 58.86; H, 5.21; N, 12.25. 62 Example 1I 1) A8-Methyl-3-(6-phenyl-pyridazin-3-yl)-3,8-diaza- 2) ECbicyclo[3.2.1]octane p-toluenesulfonate 3) S1 ¹H NMR (MeOH-d₄, 300 MHz)δ 2.13 (m, 2H), 2.34 (m, 2H), 2.35 (s, 3H), 2.93 (br s, 3H), 3.23 (m,1H), 3.42 (m, 1H), 4.15 (m, 2H), 4.41 (m, 2H), 7.22 (m, 2H), 7.40 (d, J= 9.5 Hz, 1H), 7.49 (m, 3H), 7.69 (m, 2H), 7.93 (m, 2H), 7.97 (d, J =9.5 Hz, 1H); MS (DCI/NH₃) m/z 281 (M + H)⁺; Anal. Calculated forC₁₇H₂₀N₄•C₇H₈O₃S•0.7H₂O: C, 61.97; H, 6.37; N, 12.04. Found: C, 62.34;H, 6.17; N, 11.68. 63 Example 24E 1) A(2R,5R)-2-Methyl-6-(6-phenyl-pyridazin-3-yl)-2,6-diaza- 2) FBbicyclo[3.2.0]heptane Fumarate 3) RA ¹H NMR (300 MHz, CD₃OD) δ 2.01-2.18(m, 1H) 2.33 (dd, J = 13.7, 5.3 Hz, 4) S2 1H) 2.73 (s, 3H) 3.33-3.48 (m,2H) 4.11-4.19 (m, 1H) 4.21-4.28 (m, 1H) 4.30-4.38 (m, 1H) 5.14 (t, J =5.1 Hz, 1H) 6.70-6.75 (m, 3H) 6.99 (d, J = 9.5 Hz, 1H) 7.38-7.52 (m, 3H)7.86-7.95 ppm (m, 3H); MS (DCI/NH₃) m/z 267 (M + H)⁺. 64 Example 24H 1)A (2R,5R)-6-Methyl-2-(6-phenyl-pyridazin-3-yl)-2,6-diaza- 2) PDbicyclo[3.2.0]heptane fumarate 3) RA ¹H NMR (300 MHz, CD₃OD) δ ppm2.27-2.43 (m, 1H) 2.44-2.56 (m, 4) S2 J = 6.8 Hz, 1H) 2.85 (s, 3H)3.74-3.90 (m, 2H) 4.00 (dd, J = 10.7, 6.3 Hz, 1H) 4.08-4.18 (m, 1H)4.75-4.82 (m, 1H) 4.91-4.99 (m, 1H) 6.70 (s, 2H) 7.20 (d, J = 9.5 Hz,1H) 7.38-7.55 (m, 3H) 7.87-8.02 (m, 3H); MS (DCI/NH₃) m/z 267 (M + H)⁺.65 Example 20G 1) A 1,6a-Dimethyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-2) PD pyrrolo[3,4-b]pyrrole fumarate 3) RA ¹H NMR (MeOH-d₄, 300 MHz) δppm 1.59 (s, 3H), 1.90-2.02 (m, 1H), 4) S2 2.41-2.56 (m, 1H), 2.86 (s,3H), 2.91-3.02 (m, 1H), 3.34-3.56 (m, 3H), 3.65-3.72 (m, 1H), 3.77-3.86(m, 1H), 4.22 (d, J = 12.9 Hz, 1H), 6.71 (s, 3H), 7.18 (d, J = 9.5 Hz,1H), 7.40-7.53 (m, 3H), 7.90-7.96 (m, 3H); MS (DCI/NH₃) m/z 295 (M +H)⁺; Anal. C₁₈H₂₂N₄•C₄H₄O₄: C, H, N.

Example 66 3-(4-Bromophenyl)-3-chloropyridazine Example 66A6-(4-Bromo-phenyl)-4,5-dihydro-2H-pyridazin-3-one

A solution of 4-(4-bromo-phenyl)-4-oxo-butyric acid (Aldrich, 25.0 g,97.3 mmol) in EtOH (100 mL) was treated with aqueous hydrazine (Aldrich,55%, 9.1 mL, 100 mmol) at 80° C. for 2 h. The mixture was cooled to roomtemperature and the precipitate was collected by filtration and driedunder vacuum to provide the title compound (24 g, 97% yield). ¹H NMR(300 MHz, CDCl₃) δ 2.35-2.76 (m, 2H), 2.80-3.11 (m, 2H), 7.45-7.77 (m,4H), 8.55 (s, 1H); MS (DCl/NH₃) m/z 253 (M+H)⁺, 255 (M+H)⁺.

Example 66B 6-(4-Bromo-phenyl)-2H-pyridazin-3-one

The product of example 66A (24.0 g, 94.5 mmol) was dissolved in HOAc(200 mL) and treated with bromine (Aldrich, 18.81 g, 104.5 mmol) inacetic acid (20 mL) at ambient temperature. The brown mixture was thenwarmed to 100° C. for 1 h, cooled down to ambient temperature anddiluted with of water (200 mL) while stirring. The white precipitate wasisolated by filtration and dried under vacuum overnight to provide thetitle compound (25.0 g, 100%). ¹H NMR (300 MHz, CDCl₃) δ 7.07 (d, J=10.2Hz, 1H), 7.55-7.69 (m, 4H), 7.72 (d, J=9.8 Hz, 1H); MS (DCl/NH₃) m/z 251(M+H)⁺, 253 (M+H)⁺.

Example 66C 3-(4-Bromo-phenyl)-6-chloro-pyridazine

The product of example 66B (25.0 g, 99 mmol) was stirred with POCl₃ (200mL) at 100° C. for 16 h. Most of the POCl₃ was removed by distillation,and the residue was quenched by pouring onto crushed ice with vigorousstirring. The mixture was stirred for an additional 1 h. The white soldwas filtered off, washed with water and dried under vacuum to providethe title compound (26.2 g, 97 mmol, yield, 98%). ¹H NMR (300 MHz,MeOH-D₄) δ 7.64-7.78 (m, 2H), 7.86 (d, J=8.8 Hz, 1H), 7.93-8.08 (m, 2H),8.19 (d, J=9.2 Hz, 1H); MS (DCl/NH₃) m/z 269 (M+H)⁺, 271 (M+H)⁺. 273(M+H)⁺.

Examples 67-69

The product of Example 66C was coupled to the listed amine according tothe indicated method. Further processing as noted in the table belowprovided the title compounds.

Starting Example Material Conditions Resulting Compound 67 Example 6C 1)A 2-[6-(4-Bromo-phenyl)-pyridazin-3-yl]-5-methyl-octahydro- 2) FBpyrrolo[3,4-c]pyrrole bis hydrochloride 3) RA ¹H NMR (D₂O, 300 MHz) δ2.90 (s, 3H), 3.05 (m, 1H) 3.29-4.09 (m, 9H), 4) S3 7.60 (d, J = 10.2Hz, 1H), 7.67 (d, J = 8.5 Hz, 2H) 7.74 (d, J = 8.5 Hz, 2H), 8.17 (d, J =9.8 Hz, 1H); MS (DCI/NH₃) m/z 359 (M + H)⁺, 361 (M + H)⁺; Anal.Calculated for C₁₇H₁₉BrN₄•2.00HCl•2.00H₂O: C, 43.61; H, 5.38; N, 11.97.Found: C, 43.52; H, 5.12; N, 11.70. 68 Example 7J 1) A(1S,5S)-3-[6-(4-Bromo-phenyl)-pyridazin-3-yl]-3,6-diaza- 2) FBbicyclo[3.2.0]heptane bis(p-toluenesulfonate) 3) S1 ¹H NMR (MeOH-D₄, 300MHz) δ 2.33 (s, 6H), 3.68-3.89 (m, 4H), 4.28-4.36 (m, 2H), 4.60 (d, J =13.9 Hz, 1H), 5.24 (t, J = 6.3 Hz, 1H), 7.19 (d, J = 8.1 Hz, 4H) 7.65(d, J = 8.1 Hz, 4H), 7.78 (d, J = 6.6 Hz, 2H), 7.82-8.08 (m, 3H), 8.38(d, J = 9.8 Hz, 1H); MS (DCI/NH₃) m/z 331 (M + H)⁺, 333 (M + H)⁺; Anal.Calculated for C₁₅H₁₅BrN₄•2.10C₇H₈SO₃•0.50H₂O: C, 50.83; H, 4.71; N,7.98. Found: C, 50.84; H, 4.64; N, 7.66. 69 Example 7J 1) A(1S,5S)-3-[6-(4-Bromo-phenyl)-pyridazin-3-yl]-6-methyl- 2) FB3,6-diaza-bicyclo[3.2.0]heptane p-toluenesulfonate 3) RA ¹H NMR(MeOH-D₄, 300 MHz) δ 2.32 (s, 3H), 2.90 (S, 3H), 4) S1 3.43-3.81 (m,3H), 4.09-4.31 (m, 3H), 4.60 (d, J = 13.9 Hz, 1H), 5.03 (dd, J = 7.1,5.1 Hz, 1H), 7.19 (d, J = 7.8 Hz, 2H), 7.57 (d, J = 9.8 Hz, 1H),7.61-7.78 (m, 4H), 7.90 (d, J = 8.8 Hz, 2H), 8.14 (d, J = 9.5 Hz, 1H);MS (DCI/NH₃) m/z 345 (M + H)⁺, 347 (M + H)⁺; Anal. Calculated forC₁₆H₁₇BrN₄•1.40C₇H₈SO₃•0.50H₂O: C, 52.05; H, 4.94; N, 9.41. Found: C,52.31; H, 4.89; N, 9.09.

Examples 70-74

The listed diamine was coupled with 3-(6-chloropyridazin-3-yl)-1H-indolein place of 3-chloro-6-phenylpyridazine, and further processed accordingto the listed methods, to provide the title compounds.

Example Starting Material Conditions Resulting Compound 70 Example 6C 1)C 3-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]- 2) FB1H-indole Bis(trifluoroacetate) 3) S2 ¹H NMR (CH₃OH-d₄, 300 MHz) δ ppm3.32-3.49 (m, 4H), 3.68 (dd, J = 11.5, 7.1 Hz, 2H), 3.77 (dd, J = 11.5,3.1 Hz, 2H), 3.92-4.02 (m, 2H), 7.19-7.31 (m, 2H), 7.48-7.52 (m, 1H),7.65 (d, J = 9.8 Hz, 1H), 8.10 (s, 1H), 8.27 (d, J = 7.5 Hz, 1H), 8.37(d, J = 9.8 Hz, 1H); MS (DCI/NH₃) m/z 306 (M + H)⁺; Anal.C₁₈H₁₉N₅•2.15C₂F₃HO₂: C, H, N. 71 Example 121B 1) C3-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- 2) FBpyridazin-3-yl]-1H-indole Trifluoroacetate 3) S2 ¹H NMR (CH₃OH-d₄, 300MHz) δ ppm 2.99 (s, 3H), 3.36-3.98 (m, 10H), 7.17-7.32 (m, 2H), 7.50 (d,J = 7.5 Hz, 1H), 7.65 (d, J = 9.8 Hz, 1H), 8.09 (s, 1H), 8.26 (d, J =7.1 Hz, 1H), 8.35 (d, J = 9.8 Hz, 1H); MS (DCI/NH₃) m/z 320 (M + H)⁺;Anal. C₁₉H₂₁N₅•2.1C₂F₃HO₂: C, H, N. 72 Example 10 1) C(1R,5R)-3-[6-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)- 2) FBpyridazin-3-yl]-1H-indole Bis(trifluoroacetate) 3) S4 ¹H NMR (CH₃OH-d₄,300 MHz) δ ppm 3.52-3.61 (m, 1H), 3.68 (dd, J = 13.7, 5.6 Hz, 2H), 3.81(dd, J = 11.4, 5.3 Hz, 1H), 4.25 (d, J = 11.5 Hz, 1H), 4.33 (dd, J =11.2, 8.5 Hz, 1H), 4.51 (d, J = 13.6 Hz, 1H), 5.18 (d, J = 6.1 Hz, 1H),7.22-7.34 (m, 2H), 7.49-7.56 (m, 1H), 7.81 (d, J = 9.8 Hz, 1H), 8.12 (s,1H), 8.17-8.24 (m, 1H), 8.40 (d, J = 9.8 Hz, 1H); MS (DCI/NH₃) m/z 292(M + H)⁺; Anal. C₁₇H₁₇N₅•2.1CF₃CO₂H: C, H, N. 73 Example 8 1) C(1S,5S)-3-[6-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)- 2) FBpyridazin-3-yl]-1H-indole trifluoroacetate 3) S4 ¹H NMR (CH₃OH-d₄, 300MHz) δ ppm 3.46 (dd, J = 11.5, 6.4 Hz, 1H), 3.52-3.69 (m, 2H), 3.80 (dd,J = 11.4, 5.3 Hz, 1H), 4.21 (d, J = 11.2 Hz, 1H), 4.32 (dd, J = 11.0,8.6 Hz, 1H), 4.49 (d, J = 13.6 Hz, 1H), 5.10-5.18 (m, 1H), 7.16-7.31 (m,2H), 7.49 (d, J = 7.1 Hz, 1H), 7.61 (d, J = 9.8 Hz, 1H), 8.01 (s, 1H),8.18-8.29 (m, 2H); MS (DCI/NH₃) m/z 292 (M + H)⁺; Anal.C₁₇H₁₇N₅•1.6C₂F₃HO₂: C, H, N. 74 Example 10 1) C(1R,5R)-3-[6-(6-Methyl-3,6-diaza-bicyclo[3.2.0]hept-3- 2) FByl)-pyridazin-3-yl]-1H-indole fumarate 3) RA ¹H NMR (CH₃OH-d₄, 300 MHz)δ ppm 2.95 (s, 3H), 3.31-3.38 (m, 1H), 4) S4 3.43 (dd, J = 13.6, 4.7 Hz,1H), 3.51-3.62 (m, 1H), 3.93-4.04 (m, 1H), 4.13 (d, J = 11.2 Hz, 1H),4.17-4.27 (m, 1H), 4.51 (d, J = 13.6 Hz, 1H), 4.92-5.00 (m, 1H), 6.72(s, 4H), 7.11-7.24 (m, 2H), 7.33 (d, J = 9.5 Hz, 1H), 7.45 (d, J = 7.8Hz, 1H), 7.85 (s, 1H), 7.97 (d, J = 9.5 Hz, 1H), 8.31 (d, J = 7.5 Hz,1H); MS (DCI/NH₃) m/z 306 (M + H)⁺; Anal. C₁₈H₁₉N₅•2.9C₄H₄O₄: C, H, N.

Examples 75-85 The product of Example 6C was coupled with thechloropyridazines described in Examples 82A-E and processed according tothe conditions listed in the table to provide the title compounds.Example 82A 3-Chloro-6-(nitrophenyl)-pyridazine

To an ice-cold solution of 3-chloro-6-phenylpyridazine (Aldrich, 1.4 g,7.5 mmol) in conc. sulfuric acid (30 mL) was added 90% nitric acid (0.6mL, 15 mmol). After 15 min. the mixture was poured over ice (200 mL) andneutralized with 25% aq. NaOH. The resulting precipitate was collectedby filtration and dried under vacuum. The crude product (1.84 g) was a1:1:0.5 mixture of ortho:meta:para isomers.

Example 82B 3-Chloro-6-(2-nitrophenyl)-pyridazine

The crude product from Example 82A was dissolved in warm methanol (80mL) and allowed to crystallize for 18 h. The supernatant liquid wasconcentrated and the major component was isolated by columnchromatography (SiO₂, 0.5% methanol-CH₂Cl₂) to give 560 mg of the pureortho isomer (2.4 mmol, 32% yield). MS (ESI) m/z 236 (M+H)⁺.

Example 82C 3-Chloro-6-(4-nitrophenyl)-pyridazine

The precipitate (500 mg) from Example 82B was dissolved in warm ethanol(100 mL) and allowed to crystallize for 18 h. The solid was collected byfiltration and washed with cold ethanol and dried to give 75 mg of thepure para isomer (0.32 mmol, 4% yield). MS (ESI) m/z 236 (M+H)⁺.

Example 82D 3-Chloro-6-(3-nitrophenyl)-pyridazine

The supernate from Example 82C (300 mg) was concentrated to a solid (300mg), which was dissolved in warm methanol (50 mL). A cloudy solution wasobtained. The mixture was filtered and the supernate was concentrated.The resulting solid was dissolved in methanol, filtered and allowed tocrystallize for 18 h. The solid was collected by filtration and dried togive 106 mg of the pure meta isomer (0.45 mmol, 6% yield). MS (ESI) m/z236 (M+H)⁺.

Example 82E 3-Chloro-6-imidazol-1-yl-pyridazine

A solution of 3,6-dichloropyridazine (Aldrich, 300 mg, 2.0 mmol),imidazole (Aldrich, 163 mg, 2.4 mmol), and diisopropylethylamine (620mg, 4.8 mmol) in 1.5 mL 1,2-dichlorobenzene was heated in a sealed tubeto 120° C. at 330 watts for 45 min in an Emry™ Creator microwave. Thecrude reaction mixture was purified by column chromatography (SiO₂, 1%methanol-CH₂Cl₂) to give 135 mg of the title compound (0.75 mmol, 38%yield) as the major product. MS (DCl/NH₃) m/z 181 (M+H)⁺.

Example Starting Material Conditions Resulting Compound 75 Example82C 1) D 2-[6-(4-Nitro-phenyl)-pyridazin-3-yl]-octahydro- 2) FBpyrrolo[3,4-c]pyrrole ¹H NMR (MeOD-d₄, 300 MHz) δ 2.86 (dd, J = 11.5,3.7 Hz, 2H) 3.02-3.14 (m, J = 7.1, 3.4 Hz, 2H) 3.21 (dd, J = 11.4, 7.6Hz, 2H) 3.55 (dd, J = 11.4, 3.2 Hz, 2H) 3.75-3.86 (m, 2H) 7.09 (d, J =9.8 Hz, 1H) 7.98 (d, J = 9.5 Hz, 1H) 8.17-8.25 (m, 2H) 8.29-8.39 (m,2H); MS (DCI/NH₃) m/z 312 (M + H)⁺; Anal. C₁₆H₁₇N₅O₂•0.7H₂O: C, H, N. 76Example 82B 1) D 2-[6-(2-Nitro-phenyl)-pyridazin-3-yl]-octahydro- 2) FBpyrrolo[3,4-c]pyrrole fumarate 3) S2 ¹H NMR (MeOD-d₄, 300 MHz) δ3.24-3.37 (m, 4H) 3.57-3.65 (m, 2H) 3.65-3.72 (m, 2H) 3.74-3.83 (m, 2H)6.67 (s, 2H) 7.12 (d, J = 9.5 Hz, 1H) 7.62 (d, J = 9.2 Hz, 1H) 7.64-7.70(m, 2H) 7.78 (td, J = 7.5, 1.0 Hz, 1H) 7.97-8.02 (m, 1H); MS (DCI/NH₃)m/z 312 (M + H)⁺. 77 Example 82D 1) D2-[6-(3-Nitro-phenyl)-pyridazin-3-yl]-octahydro- 2) FBpyrrolo[3,4-c]pyrrole ¹H NMR (DMSO-d₆, 300 MHz) δ 2.81 (dd, J = 6.6, 4.9Hz, 3H) 2.86-2.96 (m, 1H) 3.04-3.20 (m, 1H) 3.23-3.36 (m, 2H) 3.47-3.58(m, 2H) 3.59-3.66 (m, 2H) 3.66-3.82 (m, 2H) 3.83 (s, 3H) 7.05-7.16 (m,2H) 7.75-7.86 (m, 2H); MS (DCI/NH₃) m/z 312 (M + H)⁺. 78 Example 82C 1)D 2-Methyl-5-[6-(4-nitro-phenyl)-pyridazin-3-yl]- 2) FBoctahydro-pyrrolo[3,4-c]pyrrole 3) RA ¹H NMR (MeOD-d₄, 300 MHz) δ 2.36(s, 3H) 2.57 (dd, J = 9.8, 3.7 Hz, 2H) 2.82 (dd, J = 9.8, 7.5 Hz, 2H)3.06-3.17 (m, 2H) 3.58 (dd, J = 10.9, 3.1 Hz, 2H) 3.77 (dd, J = 11.0,7.7 Hz, 2H) 7.10 (d, J = 9.5 Hz, 1H) 7.98 (d, J = 9.5 Hz, 1H) 8.17-8.27(m, 2H) 8.30-8.39 (m, 2H); MS (DCI/NH₃) m/z 326 (M + H)⁺; Anal.C₁₇H₁₉N₅O₂•0.3H₂O: C, H, N. 79 Example 82D 1) D2-Methyl-5-[6-(3-nitro-phenyl)-pyridazin-3-yl]- 2) FBoctahydro-pyrrolo[3,4-c]pyrrole 3) RA ¹H NMR (DMSO-d₆, 300 MHz) δ3.11-3.22 (m, 4H) 3.38-3.49 (m, 2H) 3.51-3.59 (m, 2H) 3.64-3.74 (m, 2H)7.44-7.75 (m, 2H) 7.79-8.00 (m, 2H) 8.97 (s, 2H); MS (DCI/NH₃) m/z 326(M + H)⁺. 80 Example 82E 1) C2-(6-Imidazol-1-yl-pyridazin-3-yl)-5-methyl-octahydro- 2) FBpyrrolo[3,4-c]pyrrole hydrochloride 3) RA ¹H NMR (MeOD-d₄, 300 MHz) δ2.97 (s, 3H) 3.35-3.51 (m, 4H) 4) S3 3.63-3.75 (m, 4H) 3.75-3.86 (m, 2H)7.28 (s, 1H) 7.30 (d, J = 9.8 Hz, 1H) 7.87 (d, J = 9.8 Hz, 1H) 7.90 (s,1H) 8.61 (s, 1H); MS (DCI/NH₃) m/z 271 (M + H)⁺; Anal. C₁₄H₁₈N₆•1.5HCl:C, H, N. 81 Example 82E 1) C2-(6-Imidazol-1-yl-pyridazin-3-yl)-octahydro- 2) FBpyrrolo[3,4-c]pyrrole bis hydrochloride 3) S3 ¹H NMR (MeOD-d₄, 300 MHz)δ 3.33-3.42 (m, 4H) 3.61-3.70 (m, 2H) 3.72-3.77 (m, 2H) 3.83-3.90 (m,2H) 7.35 (d, J = 9.8 Hz, 1H) 7.77-7.82 (m, 1H) 8.01 (d, J = 9.8 Hz, 1H)8.29-8.32 (m, 1H) 9.68 (t, J = 1.5 Hz, 1H); MS (DCI/NH₃) m/z 257 (M +H)⁺; Anal. C₁₃H₁₆N₆•2.2HCl: C, H, N.

Examples 83-85

The title compounds were prepared by coupling the listed diamine with3-(4-iodophenyl)-6-chloropyridazine (described in Example 83F) andprocessing according to the specified methods to provide the title salt.

Example 83 Example 83A 2-Bromo-1-(4-iodo-phenyl)-ethanone

A solution of bromine (79.3 g, 508 mmol) in glacial acetic acid (50 mL)was added at room temperature to a solution of1-(4-Iodo-phenyl)-ethanone (Aldrich, 125 g, 508 mmol) in glacial aceticacid (600 mL). The mixture was stirred for 10 h, then concentrated underreduced pressure and the residue was diluted with ethyl acetate (100mL), and washed with brine (3×50 mL). The organic layer wasconcentrated, and the residue was crystallized from ethyl ether toprovide the title compound as a yellow solid (150 g, 462 mmol, 91%yield). ¹H NMR (300 MHz, CDCl₃) δ 4.39 (s, 2H), 7.69 (d, J=8.5 Hz, 2H),7.87 ppm (d, J=8.5 Hz, 2H); MS (DCl/NH₃) m/z 246 (M−Br)⁺ 264(M−Br+NH₄)⁺.

Example 83B 2-[2-(4-Iodo-phenyl)-2-oxo-ethyl]-malonic acid diethyl ester

Diethyl malonate (8 g, 50 mmol) was treated with sodium hydride (1.2 g,50 mmol) in dry THF (120 mL) under nitrogen at 0° C. for 30 minutes. Asolution of the product from Example 83A (15.8 g, 48.6 mmol) in THF (30mL) was added, and the mixture stirred for 30 minutes. The reactionmixture was diluted with ethyl acetate (200 mL) and washed with brine(3×20 mL). The organic layer was concentrated to give the title compoundas oil (15 g, 36 mmol, 74% yield): ¹H NMR (300 MHz, CDCl₃) δ 1.25-1.32(m, J=7.1, 7.1 Hz, 7H), 3.57 (d, J=7.1 Hz, 2H), 4.16-4.29 (m, 4H), 7.69(d, J=8.5 Hz, 2H), 7.84 ppm (d, J=8.8 Hz, 2H); MS (DCl/NH₃) m/z 405(M+H)⁺, 422 (M+NH₄)⁺.

Example 83C 2-[2-(4-Iodo-phenyl)-2-oxo-ethyl]-malonic acid

The product of Example 83B (1 g, 2.5 mmol) was treated with NaOHsolution (1 N, 7.5 ml, 7.5 mmol) in ethanol (5 mL) at 60° C. for 1.5hours, and then filtered through a pad of diatomaceous earth. Thefiltrate was concentrated under vacuum and the residue was diluted withwater (20 mL) and acidified with HCl (6 N) to bring to pH=1. Theresulting precipitate was collected by filtration and dried to providethe title compound as white solid (730 mg, 2.1 mmol, 84% yield): ¹H NMR(300 MHz, MeOH-D₄) δ 3.58 (d, J=7.1 Hz, 2H), 3.93 (t, J=7.0 Hz, 1H),7.75 (d, J=8.5 Hz, 2H), 7.91 ppm (d, J=8.8 Hz, 2H); MS (DCl/NH₃) m/z 366(M+NH₄)⁺.

Example 83D 6-(4-Iodo-phenyl)-4,5-dihydro-2H-pyridazin-3-one

The product of Example 83C (25 g, 71.8 mmol) was treated with hydrazinehydrate (55% aq., 16 mL, ˜275 mmol) in ethanol (300 mL) at 78° C. for 60hours. The mixture was then concentrated under reduced pressure, and theresidue was stirred with water (250 mL) for 1 h. The solid was filteredand dried under vacuum to provide the title compound (20.5 g, 68.3 mmol,95.1% yield): ¹H NMR (300 MHz, CDCl₃) δ 2.62 (t, J=8.3 Hz, 2H), 2.96 (t,J=8.3 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H), 7.75 (d, J=8.8 Hz, 2H), 8.51 ppm(s, 1H); MS (DCl/NH₃) m/z 301 (M+H)⁺ 318 (M+NH₄)⁺.

Example 83E 6-(4-Iodo-phenyl)-2H-pyridazin-3-one

The product of Example 83D (20.5 g, 68.3 mmol) in glacial acetic acid(200 mL) was treated with a solution of bromine (12 g, 75 mmol) inglacial acetic acid (50 mL) at 100° C. for 1 h. The mixture was thencooled to room temperature and stirred for an additional 16 h. Most ofthe acetic acid solvent was removed under vacuum, and the residue wasstirred with water (250 mL) for 1 h. The solid was filtered and driedunder vacuum to provide the title compound (20 g, 66.7 mmol, 98% yield):¹H NMR (300 MHz, MeOH-D₄) δ 7.06 (d, J=9.8 Hz, 1H), 7.65 (d, J=8.8 Hz,2H), 7.84 (d, J=8.8 Hz, 2H), 8.01 ppm (d, J=9.8 Hz, 1H); MS (DCl/NH₃)m/z 299 (M+H)⁺.

Example 83F 3-Chloro-6-(4-iodo-phenyl)-pyridazine

The product of Example 83E (20 g, 66.7 mmol) was treated with POCl₃ (200mL) at 100° for 16 hours. Most of the POCl₃ was removed by distillation,and the residue was poured into ice (500 g) slowly while stirring. Theprecipitated solid was filtered and dried under vacuum to provide thetitle compound (19.2 g, 60.7 mmol, 91% yield): ¹H NMR (300 MHz,CHLOROFORM-D) δ ppm 7.57 (d, J=8.8 Hz, 1H), 7.76-7.83 (m, 3H), 7.85-7.91ppm (m, 2H); MS (DCl/NH₃) m/z 317 (M+H)⁺.

Example Starting Material Conditions Resulting Compound 83 Example 7 1)C (1R,5S)-6-[6-(4-Iodo-phenyl)-pyridazin-3-yl]-3,6-diaza- 2) TFAbicyclo[3.2.0]heptane Trifluoroacetate 3) S4 ¹H NMR (CH₃OH-d₄, 300 MHz)δ ppm 3.23-3.31 (m, 1H), 3.39 (dd, J = 12.4, 7.3 Hz, 1H), 3.47-3.60 (m,1H), 3.76 (d, J = 12.2 Hz, 1H), 3.82-3.93 (m, 2H), 4.32 (t, J = 8.3 Hz,1H), 5.24 (dd, J = 6.4, 3.7 Hz, 1H), 7.04 (d, J = 9.5 Hz, 1H), 7.69-7.76(m, J = 8.8 Hz, 2H), 7.86 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 9.2 Hz, 1H);MS (DCI/NH₃) m/z 379 (M + H)⁺; Anal. C₁₅H₁₅IN₄•1.15C₂F₃HO₂: C, H, N. 84Example 8 1) C (1S,5S)-3-[6-(4-Iodo-phenyl)-pyridazin-3-yl]-3,6-diaza-2) FB bicyclo[3.2.0]heptane Trifluoroacetate 3) S4 ¹H NMR (CH₃OH-d₄, 300MHz) δ ppm 3.42 (dd, J = 11.4, 6.3 Hz, 1H), 3.50-3.67 (m, 2H), 3.78 (dd,J = 11.4, 5.3 Hz, 1H), 4.20 (d, J = 11.5 Hz, 1H), 4.30 (dd, J = 11.2,8.5 Hz, 1H), 4.51 (d, J = 13.6 Hz, 1H), 5.12 (dd, J = 6.8, 5.8 Hz, 1H),7.45 (d, J = 9.5 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.8 Hz,2H), 8.08 (d, J = 9.5 Hz, 1H); MS (DCI/NH₃) m/z 379 (M + H)⁺; Anal.C₁₅H₁₅IN₄•1.85C₂F₃HO₂: C, H, N. 85 Example 8 1) C(1S,5S)-3-[6-(4-Iodo-phenyl)-pyridazin-3-yl]-6-methyl- 2) EC3,6-diaza-bicyclo[3.2.0]heptane Trifluoroacetate 3) S4 ¹H NMR (CH₃OH-d₄,300 MHz) δ ppm 3.02 (s, 3H), 3.34-3.44 (m, 1H), 3.49 (dd, J = 13.7, 4.9Hz, 1H), 3.54-3.66 (m, 1H), 4.04-4.22 (m, 3H), 4.55 (d, J = 13.9 Hz,1H), 4.92-5.01 (m, 1H), 7.35 (d, J = 9.5 Hz, 1H), 7.76 (d, J = 8.5 Hz,2H), 7.88 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 9.5 Hz, 1H); MS (DCI/NH₃)m/z 393 (M + H)⁺; Anal. C₁₆H₁₇IN₄•1.3C₂F₃HO₂: C, H, N.

Example 86 Examples 86A and 86B

The product of Example 6C (0.60 g, 2.8 mmol),3,6-dichloro-4-methylpyridazine (Aldrich, 0.60 g, 3.7 mmol), Cs₂CO₃ (1.4g, 4.2 mmol), 1,3-bis(2,6-di-1-propylphenyl)imidazolium chloride (Strem,0.12 g, 0.28 mmol), tris(dibenzylideneacetone)dipalladium (0)(Pd₂(dba)₃, Strem, 0.10 g, 0.11 mmol) were combined and the mixture wasevacuated, then purged with N₂ (three times). This reaction mixture waswarmed to 85° C., stirred for 18 h then cooled to ambient temperatureand filtered. Purification via column chromatography (SiO₂, 50% hexanesin EtOAc) yielded 0.40 g of the major regioisomer(5-(6-Chloro-5-methyl-pyridazin-3-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester, Example 86A, 1.2 mmol, 42% yield) and 0.27 g ofthe mino regioisomer(5-(6-Chloro-4-methyl-pyridazin-3-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester, Example 86B, 0.80 mmol, 28% yield). Major andminor regioisomer: MS (DCl/NH₃) m/z 339 (M+H)⁺.

Examples 86-89

A chloropyridazinyl diamine (Example 86A or 86B) (0.40 g, 1.2 mmol),phenylboronic acid (0.29 g, 2.4 mmol), aqueous Na₂CO₃ (2 M, 2 mL),tris(dibenzylideneacetone)dipalladium (0) (Pd₂(dba)₃, Strem, 43 mg,0.047 mmol) and 1,3-bis(2,6-di-1-propylphenyl)imidazolium chloride(Strem, 50 mg, 0.12 mmol) were combined and evacuated, then purged withN₂ (three times). The mixture was stirred at 85° C. for 20 h then wascooled to ambient temperature, filtered, concentrated under reducedpressure and purified via column chromatography (SiO₂, 50% hexanes inEtOAc) to provide the phenyl-substituted pyridazine. This product wasprocessed through the deprotection, methylation (if applicable) and saltformation steps according to the conditions in the table below toprovide the title compounds.

Starting Example Material Conditions Resulting Compound 86 Example86A 1) FB 2-(5-Methyl-6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4- 2)S1 c]pyrrole bis-p-toluenesulfonate ¹H NMR (300 MHz, CD₃OD) δ ppm 2.35(s, 6H), 2.39 (d, J = 1.4 Hz, 3H), 3.43 (m, 4H), 3.65 (m, 2H), 3.77 (dd,J = 11.7, 2.9 Hz, 2H), 3.95 (m, 2H), 7.22 (d, J = 8.1 Hz, 4H), 7.57 (m,6H), 7.67 (m, 4H); MS (DCI/NH₃) m/z 281 (M + H)⁺; Anal. calculated forC₁₇H₂₀N₄•2C₇H₈O₃S: C, 59.59; H, 5.81; N, 8.97. Found: C, 59.35; H, 5.74;N, 8.81. 87 Example 86A 1) FB2-Methyl-5-(5-methyl-6-phenyl-pyridazin-3-yl)-octahydro- 2) RApyrrolo[3,4-c]pyrrole bis-p-toluenesulfonate ¹H NMR (300 MHz, 3) S1CD₃OD) δ ppm 2.35 (s, 6H), 2.39 (s, 3H), 2.99 (s, 3H), 3.16 (m, 2H),3.48 (m, 2H), 3.89 (m, 6H), 7.22 (d, J = 8.1 Hz, 4H), 7.58 (m, 6H), 7.68(m, 4H); MS (DCI/NH₃) m/z 295 (M + H)⁺; Anal. calculated forC₁₈H₂₂N₄•2.25C₇H₈O₃S•H₂O: C, 57.92; H, 6.05; N, 8.01. Found: C, 57.55;H, 5.96; N, 8.31. 88 Example 86B 1) FB2-(4-Methyl-6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4- 2) S5c]pyrrole bis-L-tartrate ¹H NMR (300 MHz, CD₃OD) δ ppm 2.50 (d, J = 0.7Hz, 3H), 3.31 (m, 4H), 3.60 (m, 4H), 3.71 (m, 2H), 4.45 (s, 4H), 7.48(m, 3H), 7.80 (d, J = 0.7 Hz, 1H), 7.95 (m, 2H); MS (DCI/NH₃) m/z 281(M + H)⁺; Anal. calculated for C₁₇H₂₀N₄•2C₄H₆O₆: C, 51.72; H, 5.56; N,9.65. Found: C, 51.89; H, 5.47; N, 10.22. 89 Example 86B 1) FB2-Methyl-5-(4-methyl-6-phenyl-pyridazin-3-yl)-octahydro- 2) RApyrrolo[3,4-c]pyrrole fumarate 3) S2 ). ¹H NMR (300 MHz, CD₃OD) δ ppm2.50 (d, J = 0.7 Hz, 3H), 2.91 (s, 3H), 3.25 (m, 4H), 3.48 (m, 2H), 3.64(m, 2H), 3.71 (d, J = 11.2 Hz, 2H), 6.68 (s, 2H), 7.48 (m, 3H), 7.81 (d,J = 1.0 Hz, 1H), 7.95 (m, 2H); MS (DCI/NH₃) m/z 295 (M + H)⁺; Anal.calculated for C₁₈H₂₂N₄•C₄H₄O₄•H₂O: C, 64.09; H, 6.41; N, 13.59. Found:C, 63.78; H, 6.32; N, 13.27.

Examples 90-110 Example 905-(6-Chloro-pyridazin-3-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

The product of Example 6c (1.5 g, 7.1 mmol) was dissolved in 1,4-dioxane(35 mL). 3,6-Dichloropyridazine (Aldrich, 1.37 g, 9.2 mmol),tris(dibenzylideneacetone)dipalladium (0) (Pd₂(dba)₃, Strem, 0.28 g,0.31 mmol), 1,3-bis(2,6-di-1-propylphenyl)imidazolium chloride (Strem,0.38 g, 0.90 mmol), and Cs₂CO₃ (6.97 g, 21.2 mmol) were added and themixture was stirred at 85° C. for 18 h, then cooled to room temperature,filtered, and concentrated under vacuum. The residue was triturated with80% EtOAc-hexanes (50 mL) and the resulting solid was filtered and driedunder vacuum to give 0.81 g of the title compound (2.5 mmol, 35% yield).MS (DCl/NH₃) m/z 325 (M+H)⁺.

Examples 91-110

The General Procedures for preparing compounds described in Examples91-110 are described below.

General Procedure for Suzuki Coupling

Method G: The aryl chloride from Example 90 (5 mmol) and the listedarylboronic acid (6 mmol) were dissolved in 1,4-dioxane (50 mL). Cesiumcarbonate (14 mmol), tris(dibenzylideneacetone)dipalladium (0)(Pd₂(dba)₃, Strem, 0.3 mmol) and1,3-bis(2,6-di-1-propylphenyl)imidazolium chloride (Strem, 0.8 mmol)were added, and the mixture was stirred at 85° C. and for 20 h. Thereaction was then cooled to room temperature and concentrated undervacuum. The residue was purified by column chromatography to provide thearylated pyridazine. Deprotection and/or N-methylation, followed by saltformation according to the procedures previously described in Example31, provided the title compounds.Method H: The aryl chloride from Example 90 (1.5 mmol) and the listedarylboronic acid (3 mmol) were stirred in toluene (25 mL). AqueousNa₂CO₃ (2M, 2.5 mL), tris(dibenzylideneacetone)dipalladium (0)(Pd₂(dba)₃, Strem, 0.06 mmol) and1,3-bis(2,6-di-1-propylphenyl)imidazolium chloride (Strem, 0.15 mmol)were added, and the mixture was stirred at 85° C. for 16 h. The mixturewas then cooled to ambient temperature, filtered through diatomaceousearth and concentrated under reduced pressure. The residue was purifiedby column chromatography to provide the arylated pyridazine.Deprotection and/or N-methylation, followed by sal formation accordingto the procedures previously described in Example 31, provided the titlecompounds.Method I: The aryl chloride from Example 90 (0.6 mmol) and the listedarylboronic acid (0.66 mmol) were combined in dioxane (15 mL). Cesiumcarbonate (0.72 mmol), tris(dibenzylideneacetone)dipalladium (0)(Pd₂(dba)₃, Strem, 9 μmol) and Bu₃P (Strem, 70 μL of 10 wt % in hexanes,24 μmol) were added, and the mixture was warmed to 95° C. for 18 h. Thereaction mixture was cooled to room temperature, filtered throughdiatomaceous earth and concentrated under reduced pressure. The crudematerial was purified by column chromatography to provide the arylatedpyridazine. Deprotection and/or N-methylation, followed by saltformation according to the procedures previously described in Example31, provided the title compounds.Method MW: The aryl halide from Example 90 (0.5 mmol) and thearylboronic acid or arylboronic ester (1.5 mmol) were dissolved indioxane-ethanol (1:1, 2 mL).Dichlorobis(triphenylphosphine)-palladium(II) (Aldrich, 0.05 mmol) and2-(dicyclohexylphosphino)biphenyl (Strem, 0.0125 mmol) were addedfollowed by 1 N Na₂CO_(3 (aq)) (1 mL) and the suspension was stirred for5 minutes. The reaction mixture was heated in a sealed tube to 150° C.at 330 Watts for 10 min. in an Emry™ Creator microwave. The reaction wasthen cooled to room temperature and concentrated under vacuum. Theresidue was purified by HPLC (Xterra C₁₈ 30, X 100 mm). The salt wasprepared according to the procedures previously described in Example 31,to provide the title compounds.

Example Boronic Acid Conditions Resulting Compound 91 o-tolyl boronicacid 1) H 2-(6-o-Tolyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4- 2) FBc]pyrrole bis-trifluoroacetate 3) S4 ¹H NMR (300 MHz, CD₃OD) δ 2.36 (s,3H), 3.25 (m, 2H), 3.39 (m, 2H), 3.66 (m, 2H), 3.75 (dd, J = 11.7, 3.2Hz, 2H), 3.90 (m, 2H), 7.39 (m, 4H), 7.52 (d, J = 9.5 Hz, 1H), 7.89 ppm(d, J = 9.5 Hz, 1H); MS (DCI/NH₃) m/z 281 (M + H)⁺; Anal. calculated forC₁₇H₂₀N₄•2CF₃CO₂H: C, 49.61; H, 4.36; N, 11.02. Found: C, 50.09; H,4.47; N, 11.24. 92 m-tolyl boronic acid 1) G2-(6-(3-methylphenyl)pyridazin-3-yl)-octahydro- 2) FBpyrrolo[3,4-c]pyrrole Bis(trifluoroacetate) 3) S4 ¹H NMR (CH₃OH-d₄, 300MHz) δ 2.44 (m, 3H), 3.30 (m, 1H), 3.40 (m, 3H), 3.66 (m, 2H), 3.76 (m,2H), 3.91 (m, 2H), 7.36 (m, 1H), 7.43 (m, 1H), 7.54 (d, J = 9.8 Hz, 1H),7.70 (m, 1H), 7.79 (m, 1H), 8.22 (d, J = 9.8 Hz, 1H); MS (DCI/NH₃) m/z281 (M + H)⁺; Anal. C₁₇H₂₀N₄•2CF₃CO₂H: C, H, N. 93 p-tolyl boronicacid 1) G 2-(6-p-Tolyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4- 2) FBc]pyrrole trifluoroacetate 3) S4 ¹H NMR (300 MHz, CD₃OD) δ 2.42 (s, 3H),3.40 (m, 4H), 3.66 (m, 2H), 3.75 (dd, J = 11.9, 3.4 Hz, 2H), 3.91 (m,2H), 7.36 (m, 2H), 7.54 (d, J = 9.8 Hz, 1H), 7.85 (m, 2H), 8.22 ppm (d,J = 9.8 Hz, 1H); MS (DCI/NH₃) m/z 281 (M + H)⁺; Anal. calculated forC₁₇H₂₀N₄•1.9CF₃CO₂H: C, 50.27; H, 4.44; N, 11.27. Found: C, 50.23; H,4.52; N, 11.57. 94 3,5- 1) G 2-[6-(3,5-Dimethyl-phenyl)-pyridazin-3-yl]-dimethylphenylboronic 2) FB octahydro-pyrrolo[3,4-c]pyrroletrifluoroacetate acid 3) S4 ¹H NMR (300 MHz, CD₃OD) δ ppm 2.40 (s, 6H),3.38 (m, 4H), 3.66 (m, 2H), 3.75 (dd, J = 11.7, 3.2 Hz, 2H), 3.92 (m,2H), 7.20 (s, 1H), 7.56 (d, J = 9.5 Hz, 1H), 7.56 (s, 2H), 8.23 (d, J =9.5 Hz, 1H); MS (DCI/NH₃) m/z 295 (M + H)⁺; Anal. calculated forC₁₈H₂₂N₄•2CF₃CO₂H: C, 50.58; H, 4.63; N, 10.72. Found: C, 50.66; H,4.56; N, 10.66. 95 p-methoxyphenyl 1) H2-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-octahydro- boronic acid 2) FBpyrrolo[3,4-c]pyrrole hydrochloride 3) S3 ¹H NMR (CH₃OH-d₄, 300 MHz) δ3.35 (m, 2H), 3.43 (m, 2H), 3.66 (m, 2H), 3.77 (m, 2H), 3.88 (s, 3H),3.97 (m, 2H), 7.11 (m, 2H), 7.72 (d, J = 9.8 Hz, 1H), 7.93 (m, 2H), 8.37(d, J = 9.8 Hz, 1H); MS (DCI/NH₃) m/z 297 (M + H)⁺; Anal. calculated forC₁₇H₂₀N₄•3HCl: C, 50.32; H, 5.71; N, 13.81. Found: C, 50.42; H, 6.11; N,13.71. 96 Furan-3-yl boronic acid 1) H2-(6-Furan-3-yl-pyridazin-3-yl)-octahydro- 2) FB pyrrolo[3,4-c]pyrrolebis-trifluoroacetate 3) S4 ¹H NMR (300 MHz, CD₃OD) δ ppm 3.39 (m, 4H),3.65 (m, 2H), 3.74 (dd, J = 11.7, 3.2 Hz, 2H), 3.92 (m, 2H), 7.00 (dd, J= 1.7, 0.7 Hz, 1H), 7.56 (d, J = 9.8 Hz, 1H), 7.69 (t, J = 1.7 Hz, 1H),8.10 (d, J = 9.5 Hz, 1H), 8.29 (m, 1H); MS (DCI/NH₃) m/z 257 (M + H)⁺;Anal. calculated for C₁₄H₁₆N₄O•2CF₃CO₂H: C, 44.64; H, 3.75; N, 11.57.Found: C, 44.49; H, 3.70; N, 11.42. 97 Thiophen-3-yl boronic 1)H2-(6-Thiophen-3-yl-pyridazin-3-yl)-octahydro- acid 2)FBpyrrolo[3,4-c]pyrrole p-toluenesulfonate 3)S1 ¹H NMR (300 MHz, CD₃OD) δppm 2.33 (s, 3H), 3.32 (m, 4H), 3.64 (m, 2H), 3.71 (m, 2H), 3.82 (m,2H), 7.21 (m, 2H), 7.27 (d, J = 9.5 Hz, 1H), 7.56 (dd, J = 5.1, 3.1 Hz,1H), 7.68 (m, 3H), 8.00 (m, 2H); MS (DCI/NH₃) m/z 273 (M + H)⁺; Anal.calculated for C₁₄H₁₆N₄S•C₇H₈O₃S•0.5H₂O: C, 54.53; H, 5.42; N, 10.38.Found: C, 54.58; H, 5.25; N, 10.58. 98 Thiophen-3-yl boronic 1)H2-Methyl-5-(6-thiophen-3-yl-pyridazin-3-yl)- acid 2)FBoctahydro-pyrrolo[3,4-c]pyrrole p-toluenesulfonate 3)RA ¹H NMR (300 MHz,CD₃OD) δ ppm 2.36 (s, 3H), 2.94 (s, 3H), 4)S1 3.26 (m, 2H), 3.38 (m,2H), 3.64 (m, 4H), 3.77 (m, 2H), 7.14 (d, J = 9.5 Hz, 1H), 7.22 (m, 2H),7.53 (dd, J = 5.1, 3.1 Hz, 1H), 7.70 (m, 3H), 7.88 (d, J = 9.5 Hz, 1H),7.93 (dd, J = 2.9, 1.2 Hz, 1H); MS (DCI/NH₃) m/z 287 (M + H)⁺; Anal.calculated for C₁₅H₁₈N₄S•C₇H₈O₃S: C, 57.62; H, 5.71; N, 12.22. Found: C,57.49; H, 5.71; N, 12.07. 99 5-indolyl boronic acid 1) I5-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- 2) FBpyridazin-3-yl]-1H-indole Bis(p-toluenesulfonate) 3) S1 ¹H NMR(CH₃OH-d₄, 300 MHz) δ ppm 2.31 (s, 7.5H), 3.23-3.50 (m, 4H), 3.58-3.72(m, 2H), 3.78 (dd, J = 11.7, 2.2 Hz, 2H), 3.95 (dd, J = 11.2, 6.8 Hz,2H), 6.63 (d, J = 3.1 Hz, 1H), 7.19 (d, J = 7.8 Hz, 5H), 7.39 (d, J =3.1 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.64-7.77 (m, 7H), 8.19 (s, 1H),8.41 (d, J = 9.8 Hz, 1H); MS (DCI/NH₃) m/z 306 (M + H)⁺; Anal.C₁₈H₁₉N₅•2.3C₇H₈O₃S: C, H, N. 100 N-=methylindol-5-yl 1) I5-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- boronic acid 2) FBpyridazin-3-yl]-1-methyl-1H-indole Fumarate 3) S2 ¹H NMR (CH₃OH-d₄, 300MHz) δ ppm 3.19-3.39 (m, 4H), 3.56-3.79 (m, 6H), 3.84 (s, 3H), 6.52 (dd,J = 3.1, 0.7 Hz, 1H), 6.67 (s, 3H), 7.12 (d, J = 9.5 Hz, 1H), 7.21 (d, J= 3.1 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.78 (dd, J = 8.5, 1.7 Hz, 1H),7.92 (d, J = 9.5 Hz, 1H), 8.09 (d, J = 1.4 Hz, 1H); MS (DCI/NH₃) m/z 320(M + H)⁺; Anal. C₁₉H₂₁N₅•1.3C₄H₄O₄•NH₄O: C, H, N. 102 o-tolyl boronicacid 1) H 2-Methyl-5-(6-o-tolyl-pyridazin-3-yl)-octahydro- 2) FBpyrrolo[3,4-c]pyrrole bis-L-tartrate 3) RA ¹H NMR (300 MHz, CD₃OD) δ ppm2.31 (s, 3H), 2.94 (s, 3H), 4) S5 3.26 (m, 2H), 3.40 (m, 2H), 3.67 (m,4H), 3.80 (m, 2H), 4.45 (s, 4H), 7.17 (d, J = 9.5 Hz, 1H), 7.32 (m, 4H),7.56 (d, J = 9.5 Hz, 1H); MS (DCI/NH₃) m/z 295 (M + H)⁺; Anal.calculated for C₁₈H₂₂N₄•2 C₄H₆O₆: C, 52.52; H, 5.76; N, 9.42. Found: C,52.29; H, 5.82; N, 9.42. 103 m-tolyl boronic acid 1) G2-Methyl-5-(6-(3-methylphenyl)pyridazin-3-yl)- 2) FBoctahydro-pyrrolo[3,4-c]pyrrole dihydrochloride 3) RA ¹H NMR (CH₃OH-d₄,300 MHz) δ 2.45 (s, 3H), 2.96 and 4) S3 3.02 (rotamer s, 3H), 3.20 (m,1H), 3.48 (m, 2H), 3.61 (m, 1H), 3.79 (m, 1H), 3.98 (m, 5H), 7.44 (m,2H), 7.81 (m, 3H), 8.41 and 8.44 (rotamer d, J = 9.8 Hz, 1H); MS(DCI/NH₃) m/z 295 (M + H)⁺; Anal. C₁₈H₂₂N₄•2.5HCl•0.5H₂O: C, H, N. 104p-tolyl boronic acid 1) G2-Methyl-5-(6-p-tolyl-pyridazin-3-yl)-octahydro- 2) S3pyrrolo[3,4-c]pyrrole di-hydrochloride ¹H NMR (300 MHz, CD₃OD) δ ppm2.43 (s, 3H), 2.97 (s, 3H), 3.17 (m, 2H), 3.54 (m, 2H), 3.93 (m, 6H),7.40 (d, J = 7.8 Hz, 2H), 7.76 (m, 1H), 7.88 (m, 2H), 8.38 (d, J = 9.5Hz, 1H); MS (DCI/NH₃) m/z 295 (M + H)⁺; Anal. calculated forC₁₈H₂₂N₄•2HCl•1.7H₂O: C, 54.33; H, 6.94; N, 14.08. Found: C, 54.79; H,7.01; N, 13.65. 105 3,5-dimethylphenyl 1) G2-[6-(3,5-Dimethyl-phenyl)-pyridazin-3-yl]-5- boronic acid 2) FBmethyl-octahydro-pyrrolo[3,4-c]pyrrole di- 3) RA hydrochloride 4) S3 ¹HNMR (300 MHz, CD₃OD) δ ppm 2.41 (s, 6H), 2.97 (s, 3H), 3.17 (m, 1H),3.52 (m, 3H), 3.91 (m, 6H), 7.25 (s, 1H), 7.58 (s, 2H), 7.78 (t, J = 9.2Hz, 1H), 8.39 (m, 1H); MS (DCI/NH₃) m/z 309 (M + H)⁺; Anal. calculatedfor C₁₉H₂₄N₄•2HCl•1.7H₂O: C, 55.39; H, 7.19; N, 13.60. Found: C, 55.21;H, 7.37; N, 13.51. 106 Furan-3-yl boronic acid 1)H2-(6-Furan-3-yl-pyridazin-3-yl)-5-methyl-octahydro- 2)FBpyrrolo[3,4-c]pyrrole bis-p-toluenesulfonate 3)RA ¹H NMR (300 MHz,CD₃OD) δ ppm 2.32 (s, 6H), 2.99 (s, 3H), 4)S1 3.19 (m, 1H), 3.49 (m,3H), 3.91 (m, 6H), 6.97 (m, 1H), 7.19 (d, J = 8.1 Hz, 4H), 7.65 (m, 5H),7.72 (m, 1H), 8.12 (dd, J = 27.8, 9.8 Hz, 1H), 8.32 (d, J = 5.8 Hz, 1H);MS (DCI/NH₃) m/z 271 (M + H)⁺; Anal. calculated for C₁₅H₁₈N₄O•2C₇H₈O₃S:C, 56.66; H, 5.57; N, 9.11. Found: C, 56.61; H, 5.56; N, 8.81. 1071-(4-methylbenzene- 1) I 5-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-sulfonyl)indol-5- 2) FB pyridazin-3-yl]-1-(toluene-4-sulfonyl)-1H-indoleboronic acid 3) S1 ¹H NMR (300 MHz, CD₃OD) δ 2.27 (s, 6H), 2.35 (s, 3H),3.37-3.51 (m, 4H), 3.57-3.72 (m, 2H), 3.80 (dd, J = 11.9, 2.0 Hz, 2H),3.99 (dd, J = 11.2, 6.8 Hz, 2H), 6.86 (d, J = 3.7 Hz, 1H), 7.17 (d, J =8.1 Hz, 4H), 7.34 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.1 Hz, 4H), 7.71(d, J = 9.8 Hz, 1H), 7.79 (d, J = 3.7 Hz, 1H), 7.86 (d, J = 8.5 Hz, 2H),7.92 (dd, J = 8.8, 1.7 Hz, 1H), 8.11-8.20 (m, 2H), 8.34 ppm (d, J = 9.8Hz, 1H); MS (DCI/NH3) m/z 460 (M + H)+; Anal. calculated forC₂₅H₂₅N₅O₂S•2.3C₇H₈O₃S: C, 57.69; H, 5.11; N, 8.18. Found: C, 57.34; H,4.82; N 8.41. 108 p-methoxyphenyl 1)H3-Methyl-8-(6-phenyl-pyridazin-3-yl)-3,8-diaza- boronic acid 2)FBbicyclo[4.2.0]octane L-tartrate 3)RA ¹H NMR (300 MHz, CD₃OD) δ ppm 2.22(m, 1H), 2.50 (m, 1H), 4)S1 2.80 (m, 1H), 2.88 (s, 3H), 3.00 (m, 1H),3.24 (dd, J = 13.9, 3.4 Hz, 1H), 3.55 (m, 1H), 3.75 (dd, J = 7.3, 1.9Hz, 1H), 4.07 (m, 2H), 4.39 (s, 2H), 4.68 (m, 1H), 7.07 (d, J = 9.5 Hz,1H), 7.49 (m, 3H), 7.92 (m, 2H), 7.94 (d, J = 9.2 Hz, 1H); MS (DCI/NH₃)m/z 281 (M + H)⁺; Anal. calculated for C₁₇H₂₀N₄•1.2C₄H₆O₆•1 H₂O: C,54.32; H, 6.15; N, 11.71. Found: C, 54.94; H, 6.54; N, 11.37.

Example 114-128 Example 114A2-(6-Chloro-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole

The product from Example 90 (1.5 g, 4.6 mmol) was deprotected usingMethod FB to give 1.02 g of the title compound (4.6 mmol, 100% yield).¹H NMR (300 MHz, CD₃OD) δ 2.78 (dd, J=11, 4 Hz, 2H) 2.97-3.06 (m, 2H)3.09-3.18 (m, 2H) 3.42 (dd, J=11, 4 Hz, 2H) 3.63-3.75 (m, 2H) 7.02 (d,J=9 Hz, 1H) 7.40 ppm (d, J=9 Hz, 1H). MS m/z 225 (M+H)⁺.

Example 114B2-(6-Chloro-pyridazin-3-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole

The product from Example 114A (1.0 g, 4.5 mmol) was N-methylated usingmethod EC to give 1.0 g of the title compound (4.4 mmol, 96% yield). HNMR (300 MHz, CD₃OD) δ 2.34 (s, 3H) 2.52 (dd, J=10, 4 Hz, 2H) 2.73-2.84(m, 2H) 3.01-3.14 (m, 2H) 3.47 (dd, J=11, 3 Hz, 2H) 3.57-3.73 (m, 2H),7.03 (d, J=9 Hz, 1H) 7.40 ppm (d, J=9 Hz, 1H). MS (DCl/NH₃) m/z 239(M+H)⁺.

Examples 115-127

The aryl halide from Example 114B (0.5 mmol) and the arylboronic acid orarylboronic ester (1.5 mmol) were processed according to the procedureof method MW, and the product carried further through the listedprocedures to provide the title compounds.

Example Boronic Acid Conditions Resulting Compound 115 5-indolyl boronicacid 1. I 5-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2- (Frontier) 2.S2 yl)-pyridazin-3-yl]-1H-indole fumarate ¹H NMR (CH₃OH-d₄, 300 MHz) δppm 2.87 (s, 3H), 3.18-3.43 (m, 4H), 3.51-3.70 (m, 4H), 3.72-3.81 (m,2H), 6.54 (d, J = 3.4 Hz, 1H), 6.69 (s, 2H), 7.17 (d, J = 9.5 Hz, 1H),7.29 (d, J = 3.4 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.72 (dd, J = 8.5,1.7 Hz, 1H), 7.94 (d, J = 9.5 Hz, 1H), 8.10 (d, J = 1.7 Hz, 1H); MS(DCI/NH₃) m/z 320 (M + H)⁺; Anal. C₁₉H₂₁N₅•1.2C₄H₄O₄•H₂O: C, H, N. 1163-Methyl-5-(4,4,5,5- 1. I 3-Methyl-5-[6-(5-methyl-hexahydro-pyrrolo[3,4-tetramethyl- 2. S2 c]pyrrol-2-yl)-pyridazin-3-yl]-1H-indole fumarate[1,3,2]dioxaborolan-2- ¹H NMR (CH₃OH-d₄, 300 MHz) δ ppm 2.36 (s, 3H),2.88 (s, 3H), yl)-1H-indole 3.21-3.38 (m, 4H), 3.54-3.68 (m, 4H),3.74-3.81 (m, 2H), 6.69 (s, 2H), 7.05 (d, J = 1.0 Hz, 1H), 7.17 (d, J =9.5 Hz, 1H), 7.42 (dd, J = 8.5, 0.7 Hz, 1H), 7.70 (dd, J = 8.5, 1.7 Hz,1H), 7.96 (d, J = 9.5 Hz, 1H), 8.05 (dd, J = 1.7, 0.7 Hz, 1H); MS(DCI/NH₃) m/z 334 (M + H)⁺; Anal. C₁₉H₂₁N₅•1.2C₄H₄O₄0.3H₂O: C, H, N. 1173-amino-4- 1. H 2-Methyl-5-[6-(5-methyl-hexahydro-pyrrolo[3,4-methylphenyl boronic 2. S2 c]pyrrol-2-yl)-pyridazin-3-yl]-phenylamineacid (Lancaster) hemifumarate ¹H NMR (CH₃OH-d₄, 300 MHz) δ ppm 2.20 (s,3H), 2.71 (s, 3H), 3.02 (dd, J = 10.5, 4.1 Hz, 2H), 3.18-3.41 (m, 4H),3.59-3.74 (m, 4H), 6.66 (s, 1H), 7.05-7.19 (m, 3H), 7.30 (d, J = 1.4 Hz,1H), 7.79 (d, J = 9.5 Hz, 1H); MS (DCI/NH₃) m/z 310 (M + H)⁺; Anal.C₁₈H₂₃N₅•0.6C₄H₄O₄•0.9H₂O: C, H, N. 118 4-aminophenyl boronic 1. H4-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2- acid (Asymchem) 2. S2yl)-pyridazin-3-yl]-phenylamine Fumarate ¹H NMR (CH₃OH-d₄, 300 MHz) δppm 2.90 (s, 3H), 3.22-3.40 (m, 4H), 3.55-3.67 (m, 4H), 3.71-3.79 (m,2H), 6.69 (s, 2H), 6.75-6.82 (m, 2H), 7.12 (d, J = 9.5 Hz, 1H),7.64-7.72 (m, 2H), 7.80 (d, J = 9.5 Hz, 1H); MS (DCI/NH₃) m/z 296 (M +H)⁺; Anal. C₁₇H₂₁N₅•1.3C₄H₄O₄•0.5H₂O: C, H, N. 119 4-indolyl boronicacd 1. I 4-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2- (Apollo) 2. S2yl)-pyridazin-3-yl]-1H-indole Trifluoroacetate ¹H NMR (CH₃OH-d₄, 300MHz) δ ppm 2.99 (s, 3H), 3.21-4.00 (m, 10H), 6.88 (d, J = 2.4 Hz, 1H),7.27-7.35 (m, 1H), 7.42-7.52 (m, 2H), 7.63 (d, J = 8.1 Hz, 1H), 7.69 (d,J = 9.5 Hz, 1H), 8.38 (d, J = 9.8 Hz, 1H); MS (DCI/NH₃) m/z 320 (M +H)⁺; Anal. C₁₉H₂₁N₅•2.15C₂F₃HO₂: C, H, N. 120 2-Benzofuran boronic acid3. I 2-(6-Benzofuran-2-yl-pyridazin-3-yl)-5-methyl- (Aldrich) 4. S2octahydro-pyrrolo[3,4-c]pyrrole Trifluoroacetate ¹H NMR (CH₃OH-d₄, 300MHz) δ ppm 2.98 (s, 3H), 3.33-4.08 (m, 10H), 7.26-7.43 (m, 3H), 7.52 (s,1H), 7.59 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 8.12 (d, J =9.5 Hz, 1H); MS (DCI/NH₃) m/z 321 (M + H)⁺; Anal. C₁₉H₂₀N₄O•2.1C₂F₃HO₂:C, H, N. 122 2-amino-5-pyridinyl 1)MW5-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2- boronic acid 2)S3yl)-pyridazin-3-yl]-pyridin-2-ylamine ¹H NMR (300 MHz, CD₃OD) δ ppm 2.35(s, 3H) 2.52 (dd, J = 10, 4 Hz, 2H) 2.78-2.89 (m, 2H) 3.02-3.16 (m, 2H)3.47-3.58 (m, 2H) 3.62-3.75 (m, 2H) 6.67 (d, J = 8 Hz, 1H) 7.05 (d, J =10 Hz, 1H) 7.76 (d, J = 9 Hz, 1H) 8.05 (dd, J = 9, 3 Hz, 1H) 8.45 (s,1H); MS (DCI/NH₃) m/z 297 (M + H)⁺; Anal; C₁₆H₂₀N₆•3.6HCl•1.38H₂O 123Pyrrole-3-boronic acid 1)MW2-Methyl-5-[6-(1H-pyrrol-3-yl)-pyridazin-3-yl]- 2)DeSioctahydro-pyrrolo[3,4-c]pyrrole 3)S3 ¹H NMR (300 MHz, CD₃OD) δ ppm 2.34(s, 3H) 2.48 (dd, J = 10, 4 Hz, 2H) 2.80-2.91 (m, 2H) 3.00-3.13 (m, 2H)3.46-3.56 (m, 2H) 3.56-3.70 (m, 2H) 6.59-6.66 (m, 1H) 6.75-6.83 (m, 1H)7.00 (d, J = 9 Hz, 1H) 7.28-7.37 (m, 1H) 7.62 (d, J = 9 Hz, 1H); MS(DCI/NH₃) m/z 270 (M + H)⁺. 124 Thiphen-2-yl boronic 1)MW2-Methyl-5-(6-thiophen-2-yl-pyridazin-3-yl)- acid 2)S3octahydro-pyrrolo[3,4-c]pyrrole ¹H NMR (300 MHz, CD₃OD) δ ppm 2.35 (s,3H) 2.53 (dd, J = 10, 4 Hz, 2H) 2.75-2.90 (m, 2H) 3.01-3.15 (m, 2H)3.48-3.58 (m, 2H) 3.63-3.75 (m, 2H) 7.04 (d, J = 9 Hz, 1H) 7.11 (d, J =9 Hz, 1H) 7.43 (d, J = 6 Hz, 1H) 7.54 (d, J = 5 Hz, 1H) 7.81 (d, J = 9Hz, 1H); MS (DCI/NH₃) m/z 287 (M + H)⁺; Anal; C₁₅H₁₈N₄S•3.5HCl•0.19H₂O125 Pyrazol-4-yl boronic 1)MW2-Methyl-5-[6-(1H-pyrazol-4-yl)-pyridazin-3-yl]- acid 2)S3octahydro-pyrrolo[3,4-c]pyrrole ¹H NMR (300 MHz, CD₃OD) δ ppm 2.35 (s,3H) 2.52 (dd, J = 10, 4 Hz, 2H) 2.79-2.90 (m, 2H) 3.02-3.15 (m, 2H)3.49-3.58 (m, 2H) 3.62-3.72 (m, 2H) 7.04 (d, J = 9 Hz, 1H) 7.69 (d, J =9 Hz, 1H) 8.11 (bs, 2H); MS (DCI/NH₃) m/z 271 (M + H)⁺; Anal;C₁₄H₁₈N₆•4.08HCl•0.46C₄H₈O₂ 126 3-carbazole boronic 1)MW3-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2- acid 2)S3yl)-pyridazin-3-yl]-9H-carbazole ¹H NMR (300 MHz, CD₃OD) δ ppm 2.37 (s,3H) 2.55 (dd, J = 11, 3 Hz, 2H) 2.82-2.94 (m, 2H) 3.05-3.17 (m, 2H)3.54-3.63 (m, 2H) 3.66-3.79 (m, 2H) 7.12 (d, J = 9 Hz, 1H) 7.17-7.23 (m,1H) 7.34-7.50 (m, 2H) 7.54 (d, J = 8 Hz, 1H) 7.93-8.04 (m, 2H) 8.13 (d,J = 8 Hz, 1H) 8.61 (s, 1H); ); MS (DCI/NH₃) m/z 370 (M + H)⁺; Anal;C₂₃H₂₃N₅•4.62HCl•0.87CH₃OH 127 Furyl-2-boronic acid 1)MW2-(6-Furan-2-yl-pyridazin-3-yl)-5-methyl- 2)S3octahydro-pyrrolo[3,4-c]pyrrole ¹H NMR (300 MHz, CD₃OD) δ ppm 2.34 (s,3H) 2.52 (dd, J = 10, 4 Hz, 2H) 2.75-2.90 (m, 2H) 3.03-3.16 (m, 2H)3.50-3.60 (m, 2H) 3.64-3.78 (m, 2H) 6.54-6.62 (m, J = 13 Hz, 1H)6.98-7.02 (m, 1H) 7.05 (d, J = 9 Hz, 1H) 7.64 (s, 1H) 7.75 (d, J = 9 Hz,1H); MS (DCI/NH₃) m/z 271 (M + H)⁺; Anal; C₁₅H₁₈N₄O•3.05HCl•0.98CH₃OH

Example 128 Example 128A5-(5-Bromo-pyridin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

To a solution of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acidtert-butyl ester (7.0317 g, 33.2 mmol) in 180 mL toluene was added2,5-dibromopyridine (22.03 g, 92.9 mmol),tris(dibenzylidenacetone)dipalladium (0) (Pd₂(dba)₃, Strem, 0.6087 g,0.664 mmol), 2,2′-bis(diphenyphosphino)-1,1′binaphthyl (BINAP, Aldrich,1.0506 g, 1.68 mmol), and NaOtBu (Aldrich, 4.778 g, 49.7 mmol. Thereaction mixture was heated to 90° C. under dry N₂ for 6 hours. Thereaction mixture was cooled to room temperature and was filtered throughdiatomaceous earth and the residue was washed with 250 mL ethyl acetate.The combined organic extracts were concentrated under reduced pressure.The residue was purified via column chromatography (SiO₂, gradient 5% to60% EtOAc-hexanes) to give 7.71 g (20.6 mmol, 62% yield). H NMR (300MHz) δ 1.45 (s, 9H) 2.94-3.14 (m, 2H) 3.17-3.38 (m, 4H) 3.51-3.76 (m,4H) 6.46 (d, J=9 Hz, 1H) 7.59 (dd, J=9, 3 Hz, 1H) 8.05 ppm (s, 1H)

Example 128B 2-(5-Bromo-pyridin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole

The product from Example 128A (7.6 g, 21 mmol) was deprotected usingMethod FB to give 5.5 g of the title compound (21 mmol, 100% yield). HNMR (300 MHz, CD₃OD) δ 2.75 (dd, J=11, 4 Hz, 2H) 2.90-3.02 (m, 2H)3.07-3.17 (m, 2H) 3.34-3.38 (m, 2H) 3.51-3.63 (m, 2H) 6.49 (d, J=9 Hz,1H) 7.59 (dd, J=9, 3 Hz, 1H) 8.05 ppm (s, 1H). MS (DCl/NH₃) m/z 270(M+H)⁺.

Example 128C2-(5-Bromo-pyridin-2-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole

The product from Example 128B (5.5 g, 20 mmol) was N-methylated usingmethod EC to give 4.7 g of the title compound (1.7 mmol, 82% yield). HNMR (300 MHz, CD₃OD) δ 2.29-2.36 (m, 3H) 2.45 (dd, J=10, 4 Hz, 2H)2.73-2.90 (m, 2H) 2.97 (s, 2H) 3.34-3.43 (m, 2H) 3.48-3.58 (m, 2H) 6.51(d, J=9 Hz, 1H) 7.59 (dd, J=9, 3 Hz, 1H) 8.06 ppm (s, 1H). MS (DCl/NH₃)m/z 283 (M+H)⁺.

Examples 131-132

The product of Example 128A was coupled with the indicated boronic acid,and further processed according to the indicated procedures, to providethe title compound.

Example Boronic Acid Conditions Resulting Compound 131 phenyl boronicacid 1) H 2-(5-Phenyl-pyridin-2-yl)-octahydro-pyrrolo[3,4- 2) FBc]pyrrole trifluoroacetate 3) S4 ¹H NMR (CH₃OH-d₄, 300 MHz) δ 3.33 (brd, J = 4.4 Hz, 1H), 3.37 (m, 1H), 3.44 (m, 1H), 3.70 (m, 4H), 3.92 (m,2H), 7.08 (d, J = 9.5 Hz, 1H), 7.52 (m, 3H), 7.65 (m, 2H), 8.18 (br d, J= 2.4 Hz, 1H), 8.25 (dd, J = 9.5, 2.4 Hz, 1H); MS (DCI/NH₃) m/z 266 (M +H)⁺; Anal. calculated for C₂₀H₂₁N₃S•2.1CF₃CO₂H: C, 50.44; H, 4.21; N,8.32. Found: C, 50.57; H, 4.38; N, 8.32. 132 phenyl boronic acid 1) H2-(5-Phenyl-pyridin-2-yl)-octahydro-pyrrolo[3,4- 2) RA c]pyrroletrifluoroacetate 3) FB The product of Example 20A (0.20 g, 0.55 mmol) in5 mL 4) S4 CH₂Cl₂ was treated with 5 mL TFA as described in Example 11Dto give 0.233 g of the title compound (0.46 mmol, 84% yield). ¹H NMR(CH₃OH-d₄, 300 MHz) δ 3.33 (br d, J = 4.4 Hz, 1H), 3.37 (m, 1H), 3.44(m, 1H), 3.70 (m, 4H), 3.92 (m, 2H), 7.08 (d, J = 9.5 Hz, 1H), 7.52 (m,3H), 7.65 (m, 2H), 8.18 (br d, J = 2.4 Hz, 1H), 8.25 (dd, J = 9.5, 2.4Hz, 1H); MS (DCI/NH₃) m/z 266 (M + H)⁺; Anal. calculated forC₂₀H₂₁N₃S•2.1CF₃CO₂H: C, 50.44; H, 4.21; N, 8.32. Found: C, 50.57; H,4.38; N, 8.32.

Examples 133-155

The product of Example 128C was coupled with the indicated boronic acid,and further processed according to the indicated procedures, to providethe title compound.

Example Reactants Conditions Resulting Compound 133 5-pyrimidineboronic 1) MW 2-Methyl-5-(5-pyrimidin-5-yl-pyridin-2-yl)- acid 2) S4octahydro-pyrrolo[3,4-c]pyrrole ¹H NMR (300 MHz, CD₃OD) δ ppm 2.44 (s,3H) 2.57-2.70 (m, 2H) 2.91-3.03 (m, 2H) 3.04-3.23 (m, 2H) 3.44-3.58 (m,2H) 3.59-3.71 (m, 2H) 6.73 (d, J = 8 Hz, 1H) 7.86-7.97 (m, 1H) 8.42 (d,J = 2 Hz, 1H) 9.01 (s, 2H) 9.06 (s, 1H); MS (DCI/NH₃) m/z 282 (M + H)⁺;Anal. C₆H₁₉N₅•2.6CF₃CO₂H: C, H, N. 134 4-pyrazole boronic acid 1) MW2-Methyl-5-[5-(1H-pyrazol-4-yl)-pyridin-2-yl]- 2) S3octahydro-pyrrolo[3,4-c]pyrrole ¹H NMR (300 MHz, CD₃OD) δ ppm 2.34 (s,3H) 2.46 (dd, J = 10, 4 Hz, 2H) 2.79-2.93 (m, 2H) 2.98-3.11 (m, 2H) 3.44(d, J = 22 Hz, 2H) 3.51-3.60 (m, 2H) 6.63 (d, J = 8 Hz, 1H) 7.74 (dd, J= 9, 2 Hz, 1H) 7.86 (s, 2H) 8.25 (dd, J = 2, 1 Hz, 1H); MS (DCI/NH₃) m/z270 (M + H)⁺; Anal. C₁₅H₁₉N₅•3.6HCl: C, H, N. 135 3-cyanophenyl 1) MW3-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2- boronic acid 2) S3yl)-pyridin-3-yl]-benzonitrile ¹H NMR (300 MHz, CD₃OD) δ ppm 2.34 (s,3H) 2.49 (dd, J = 10, 4 Hz, 2H) 2.78-2.92 (m, 2H) 3.01-3.14 (m, 2H)3.44-3.52 (m, 2H) 3.57-3.71 (m, 2H) 6.68 (d, J = 9 Hz, 1H) 7.52-7.68 (m,2H) 7.83-7.90 (m, 2H) 7.91-7.94 (m, J = 8 Hz, 1H) 8.35 (d, J = 3 Hz,1H); MS (DCI/NH₃) m/z 305 (M + H)⁺; Anal; C₁₉H₂₀ON₄•3.3HCl•0.21H₂O 1362-methoxypyrimid-5-yl 1) MW2-[5-(2-Methoxy-pyrimidin-5-yl)-pyridin-2-yl]-5- boronic acid 2) S3methyl-octahydro-pyrrolo[3,4-c]pyrrole ¹H NMR (300 MHz, CD₃OD) δ ppm2.34 (s, 3H) 2.49 (dd, J = 10, 4 Hz, 2H) 2.78-2.90 (m, 2H) 2.98-3.12 (m,2H) 3.43-3.51 (m, 2H) 3.57-3.67 (m, 2H) 4.04 (s, 3H) 6.69 (d, J = 8 Hz,1H) 7.81 (dd, J = 9, 3 Hz, 1H) 8.29 (d, J = 3 Hz, 1H) 8.75 (s, 2H); MS(DCI/NH₃) m/z 312 (M + H)⁺; Anal; C₁₇H₂₁N₅O•2.48HCl•0.08H₂O 1373,5-dimethylpyrazol-4- 1) MW2-[5-(3,5-Dimethyl-1H-pyrazol-4-yl)-pyridin-2-yl]- yl boronic acid 2) S35-methyl-octahydro-pyrrolo[3,4-c]pyrrole ¹H NMR (300 MHz, CD₃OD) δ ppm2.20 (s, 6H) 2.35 (s, 3H) 2.46 (dd, J = 10, 4 Hz, 2H) 2.81-2.94 (m, 2H)2.98-3.13 (m, 2H) 3.41-3.50 (m, 2H) 3.51-3.62 (m, 2H) 6.66 (d, J = 9 Hz,1H) 7.48 (dd, J = 9, 2 Hz, 1H) 7.93 (s, 1H); MS (DCI/NH₃) m/z 298 (M +H)⁺; Anal; C₁₇H₂₃N₅•1.6HCl•2.3H₂O 138 1-methylpyrazol-4-yl 1) MW2-Methyl-5-[5-(1-methyl-1H-pyrazol-4-yl)-pyridin- boronic acid 2) S32-yl]-octahydro-pyrrolo[3,4-c]pyrrole ¹H NMR (300 MHz, CD₃OD) δ ppm 2.34(s, 3H) 2.46 (dd, J = 10, 4 Hz, 2H) 2.81-2.93 (m, 2H) 2.96-3.11 (m, 2H)3.39-3.48 (m, 2H) 3.50-3.60 (m, 2H) 3.91 (s, 3H) 6.62 (d, J = 9 Hz, 1H)7.62-7.76 (m, 2H) 7.85 (s, 1H) 8.22 (s, 1H); ); MS (DCI/NH₃) m/z 284(M + H)⁺; Anal; C₁₆H₂₁N₅•2.76HCl•0.16H₂O 139 3,5-dimethylisoxazol-4- 1)MW 2-[5-(3,5-Dimethyl-isoxazol-4-yl)-pyridin-2-yl]-5- yl boronic acid 2)S3 methyl-octahydro-pyrrolo[3,4-c]pyrrole ¹H NMR (300 MHz, CD₃OD) δ ppm2.26 (s, 3H) 2.43 (s, 3H) 2.97 (s, 3H) 3.11-3.23 (m, 1H) 3.38-3.53 (m,2H) 3.54-3.67 (m, 1H) 3.70-4.11 (m, 6H) 7.26 (t, J = 9 Hz, 1H) 7.96 (d,J = 18 Hz, 1H) 8.00-8.11 (m, 1H); MS (DCI/NH₃) m/z 299 (M + H)⁺; Anal;C₁₇H₂₂N₄O•2.76HCl•0.16H₂O 140 3-pyridyl boronic acid 1) MW6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- 2) S3[3,3′]bipyridinyl dihydrochloride ¹H NMR (300 MHz, CD₃OD) δ ppm 2.35 (s,3H) 2.50 (dd, J = 10, 4 Hz, 2H) 2.79-2.92 (m, 2H) 3.00-3.14 (m, 2H)3.44-3.53 (m, 2H) 3.56-3.71 (m, 2H) 6.71 (d, J = 9 Hz, 1H) 7.42-7.54 (m,1H) 7.87 (dd, J = 9, 3 Hz, 1H) 8.03 (d, J = 10 Hz, 1H) 8.35 (d, J = 2Hz, 1H) 8.45 (d, J = 6 Hz, 1H) 8.74 (s, 1H); MS (DCI/NH₃) m/z 281 (M +H)⁺; Anal; C₁₇H₂₀N₄•2.35HCl•3.27H₂O 141 4-pyridyl boronic acid 1) MW6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- 2) S3[3,4′]bipyridinyl trihydroclhloride ¹H NMR (300 MHz, CD₃OD) δ ppm 2.35(s, 3H) 2.51 (dd, J = 10, 4 Hz, 2H) 2.78-2.91 (m, 2H) 3.00-3.15 (m, 2H)3.44-3.56 (m, 2H) 3.61-3.74 (m, 2H) 6.70 (d, J = 9 Hz, 1H) 7.58-7.75 (m,2H) 7.96 (dd, J = 9, 3 Hz, 1H) 8.40-8.61 (m, 3H); MS (DCI/NH₃) m/z 281(M + H)⁺; Anal; C₁₇H₂₀N₄•3HCl•2.5H₂O 142 4-cyanophenyl 1) MW4-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2- boronic acid 2) S3yl)-pyridin-3-yl]-benzonitrile ¹H NMR (300 MHz, CD₃OD) δ ppm 2.97 (s,3H) 3.34-3.61 (m, 4H) 3.61-3.98 (m, 6H) 7.05 (d, J = 9 Hz, 1H) 7.82 (s,4H) 8.09-8.28 (m, 1H) 8.30-8.50 (m, 1H); MS (DCI/NH₃) m/z 305 (M + H)⁺.143 m-2-aminopyridine 1) MW6′-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- boronic acid 2) S3[3,3′]bipyridinyl-6-ylamine trihydrochloride ¹H NMR (300 MHz, CD₃OD) δppm 2.34 (s, 3H) 2.47 (dd, J = 10, 4 Hz, 2H) 2.81-2.92 (m, 2H) 2.98-3.11(m, 2H) 3.39-3.50 (m, 2H) 3.52-3.65 (m, 2H) 6.65 (d, J = 9 Hz, 2H)7.59-7.80 (m, 2H) 8.06 (s, 1H) 8.19 (s, 1H); MS (DCI/NH₃) m/z 296 (M +H)⁺; Anal; C₁₇H₂₁N₅•3.0HCl•2.1H₂O 144 3-pyrrolyl boronic acid 1) MW2-Methyl-5-[5-(1H-pyrrol-3-yl)-pyridin-2-yl]- 2) DeSioctahydro-pyrrolo[3,4-c]pyrrole trifluoroacetate 3) S4 ¹H NMR (300 MHz,CD₃OD) δ ppm 2.96 (s, 3H) 3.34-3.60 (m, 4H) 3.63-3.93 (m, 6H) 6.44 (s,1H) 6.83 (s, 1H) 7.12 (d, J = 9 Hz, 1H) 7.20 (s, 1H) 8.01 (s, 1H) 8.25(dd, J = 9, 2 Hz, 1H); MS (DCI/NH₃) m/z 269 (M + H)⁺; Anal;C₁₆H₂₀N₄•2.9C₂HF₃O₂•0.64H₂O 145 2-pyrrolyl boronic acid 1) MW2-Methyl-5-[5-(1H-pyrrol-2-yl)-pyridin-2-yl]- 2) FBoctahydro-pyrrolo[3,4-c]pyrrole 3) S3 ¹H NMR (300 MHz, CD₃OD) δ ppm 2.33(s, 3H) 2.45 (dd, J = 10, 4 Hz, 2H) 2.81-2.92 (m, 2H) 2.96-3.11 (m, 2H)3.39-3.47 (m, 2H) 3.49-3.60 (m, 2H) 6.07-6.15 (m, 1H) 6.26-6.36 (m, 1H)6.61 (d, J = 8 Hz, 1H) 6.71-6.80 (m, 1H) 7.73 (dd, J = 9, 3 Hz, 1H) 8.26(d, J = 3 Hz, 1H); MS (DCI/NH₃) m/z 269 (M + H)⁺; 1462-cyanopyridyl-3- 1) MW6′-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- boronic acid 2) S3[3,3′]bipyridinyl-2-carbonitrile dihydrochloride ¹H NMR (300 MHz, CD₃OD)δ ppm 2.35 (s, 3H) 2.52 (dd, J = 10, 4 Hz, 2H) 2.78-2.90 (m, 2H)3.02-3.14 (m, 2H) 3.46-3.57 (m, 2H) 3.62-3.73 (m, 2H) 6.73 (d, J = 9 Hz,1H) 7.70 (dd, J = 8, 5 Hz, 1H) 7.82 (dd, J = 9, 2 Hz, 1H) 8.02 (d, J = 8Hz, 1H) 8.31 (d, J = 3 Hz, 1H) 8.63 (d, J = 6 Hz, 1H); MS (DCI/NH₃) m/z306 (M + H)⁺; Anal; C₁₈H₁₉N₅•2.22HCl•0.26H₂O 147 3-furyl boronic acid 1)MW 2-(5-Furan-3-yl-pyridin-2-yl)-5-methyl-octahydyro- 2) S3pyrrolo[3,4-c]pyrrole dihydrochloride ¹H NMR (300 MHz, CD₃OD) δ ppm 2.34(s, 3H) 2.46 (dd, J = 10, 4 Hz, 2H) 2.80-2.92 (m, 2H) 2.98-3.10 (m, 2H)3.38-3.49 (m, 2H) 3.50-3.63 (m, 2H) 6.62 (d, J = 8 Hz, 1H) 6.68-6.76 (m,1H) 7.51-7.55 (m, 1H) 7.71 (dd, J = 9, 2 Hz, 1H) 7.79 (s, 1H) 8.22 (d, J= 2 Hz, 1H); MS (DCI/NH₃) m/z 270 (M + H)⁺; Anal;C₁₆H₁₉N₃O•2.23HCl•1.78H₂O 148 2-thienylboronic acid 1) MW2-Methyl-5-(5-thiophen-2-yl-pyridin-2-yl)- 2) S3octahydro-pyrrolo[3,4-c]pyrrole hydrochloride ¹H NMR (300 MHz, CD₃OD) δppm 2.34 (s, 3H) 2.48 (dd, J = 10, 4 Hz, 2H) 2.79-2.91 (m, 2H) 2.98-3.11(m, 2H) 3.41-3.50 (m, 2H) 3.53-3.66 (m, 2H) 6.62 (d, J = 9 Hz, 1H)7.01-7.09 (m, 1H) 7.19-7.25 (m, 1H) 7.29 (d, J = 6 Hz, 1H) 7.73-7.82 (m,1H) 8.30 (d, J = 3 Hz, 1H);); MS (DCI/NH₃) m/z 286 (M + H)⁺; Anal;C₁₆H₁₉N₃S•1.61HCl•2.3H₂O 149 3-thienylboronic acid 1) MW2-Methyl-5-(5-thiophen-3-yl-pyridin-2-yl)- 2) S3octahydro-pyrrolo[3,4-c]pyrrole dihydrochloride ¹H NMR (300 MHz, CD₃OD)δ ppm 2.34 (s, 3H) 2.47 (dd, J = 10, 4 Hz, 2H) 2.80-2.92 (m, 2H)2.98-3.12 (m, 2H) 3.39-3.50 (m, 2H) 3.52-3.66 (m, 2H) 6.64 (d, J = 9 Hz,1H) 7.34-7.40 (m, 1H) 7.43-7.51 (m, 2H) 7.83 (dd, J = 9, 2 Hz, 1H)8.29-8.38 (m, 1H); ); MS (DCI/NH₃) m/z 286 (M + H)⁺; Anal;C₁₆H₁₉N₃O•2.05HCl•2.27H₂O 150 5-benzofuran boronic 1) MW2-(5-Benzofuran-5-yl-pyridin-2-yl)-5-methyl- acid 2) S3octahydro-pyrrolo[3,4-c]pyrrole dihydrochloride ¹H NMR (300 MHz, CD₃OD)δ ppm 2.36 (s, 3H) 2.50 (dd, J = 10, 4 Hz, 2H) 2.82-2.95 (m, 2H)2.99-3.13 (m, 2H) 3.43-3.52 (m, 2H) 3.53-3.66 (m, 2H) 6.69 (d, J = 9 Hz,1H) 6.83-6.90 (m, 1H) 7.42-7.49 (m, 1H) 7.51-7.58 (m, 1H) 7.70-7.79 (m,2H) 7.85 (dd, J = 9, 2 Hz, 1H) 8.27-8.35 (m, 1H); MS (DCI/NH₃) m/z 320(M + H)⁺; Anal; C₂₀H₂₁N₃O•2.23HCl•2.02H₂O 151 2-furyl boronic acid 1) MW2-(5-Furan-2-yl-pyridin-2-yl)-5-methyl-octahydyro- 2) S3pyrrolo[3,4-c]pyrrole dihydrochloride 1H NMR (300 MHz, CD₃OD) δ ppm 2.34(s, 3H) 2.47 (dd, J = 10,4 Hz, 2H) 2.80-2.91 (m, 2H) 2.98-3.12 (m, 2H)3.40-3.51 (m, 2H) 3.54-3.66 (m, 2H) 6.44-6.49 (m, 1H) 6.55-6.58 (m, 1H)6.63 (d, J = 8 Hz, 1H) 7.46-7.52 (m, 1H) 7.81 (dd, J = 9, 2 Hz, 1H) 8.37(d, J = 2 Hz, 1H); MS (DCI/NH₃) m/z 270 (M + H)⁺; Anal;C₁₆H₁₉N₃O•2.27HCl•1.27H₂O 152 3-carbazole boronic 1) MW3-[6-(5-Methyl-hexahydyro-pyrrolo[3,4-c]pyrrol-2- acid 2) S3yl)-pyridin-3-yl]-9H-carbazole trihydrochloride ¹H NMR (300 MHz, CD₃Cl)δ ppm 2.45 (s, 3H) 2.49-2.62 (m, 2H) 2.93-3.05 (m, 2H) 3.05-3.18 (m, 2H)3.48-3.57 (m, 2H) 3.58-3.70 (m, 2H) 6.55 (d, J = 8 Hz, 1H) 7.39-7.52 (m,3H) 7.54-7.61 (m, 1H) 7.81 (dd, J = 9, 3 Hz, 1H) 8.08-8.11 (m, 1H)8.11-8.14 (m, 1H) 8.19 (s, 1H) 8.52 (d, J = 2 Hz, 1H); MS (DCI/NH₃) m/z369 (M + H)⁺; Anal; C₂₄H₂₄N₄•3.09HCl•1.96CH₃OH 153 5-indolyl boronicacid 1) I 5-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2) S2yl)-pyridin-3-yl]-1H-indole Fumarate ¹H NMR (CH₃OH-d₄, 300 MHz) δ ppm2.93 (s, 3H), 3.19-3.39 (m, 4H), 3.50 (dd, J = 10.5, 6.8 Hz, 2H),3.57-3.75 (m, 4H), 6.48 (d, J = 3.1 Hz, 1H), 6.71 (s, 3H), 6.78 (d, J =8.5 Hz, 1H), 7.25 (d, J = 3.4 Hz, 1H), 7.29 (dd, J = 8.5, 2.0 Hz, 1H),7.44 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 1.4 Hz, 1H), 7.90 (dd, J = 8.8,2.4 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H); MS (DCI/NH₃) m/z 319 (M + H)⁺;Anal. C₂₀H₂₂N₄•1.7C₄H₄O₄•0.4H₂O: C, H, N. 154 4-indolyl boronic acid 1.I 4-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2- 2. S4yl)-pyridin-3-yl]-1H-indole Trifluoroacetate ¹H NMR (CH₃OH-d₄, 300 MHz)δ ppm 2.99 (s, 3H), 3.33-4.05 (m, 10H), 6.55 (d, J = 3.1 Hz, 1H), 7.10(d, J = 7.4 Hz, 1H), 7.18 (d, J = 9.2 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H),7.36 (d, J = 3.4 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 8.32(dd, J = 9.2, 2.1 Hz, 1H); MS (DCI/NH₃) m/z 319 (M + H)⁺; Anal.C₂₀H₂₂N₄•2.1C₂F₃HO₂: C, H, N.

Example 1552-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-3-yl]-2H-pyridazin-3-one

To the product from Example 128C (0.1992 g, 0.70 mmol) was addedpyridazinone (Strem, 0.108 g, 1.13 mmol), CuI (Aldrich, 0.048 g, 0.76mmol), and K₂CO₃ (Aldrich, 0.354 g, 2.56 mmol) in 25 mL pyridine. Thereaction mixture was heated to reflux for 2 days. An additional amountof pyridazinone (0.018 g, 0.187 mmol) and CuI (0.026 g, 0.40 mmol) wasadded. The reaction was allowed to reflux an additional 3 days. Thereaction mixture was cooled to room temperature and concentrated undervacuum. The residue was partitioned between CH₂Cl₂ (50 mL) and NH₄OH aq(25 mL). The organic layer was dried over MgSO₄, concentrated andpurified via HPLC (Xterra C₁₈, 30×100 mm, gradient 20% to 70%CH₃CN/NH₄HCO₃, flow rate 40 ml/min) to give 0.145 g, (0.49 mmol, 69%yield). ¹H NMR (300 MHz, CD₃OD) □ ppm 2.34 (s, 3H) 2.49 (dd, J=10, 4 Hz,2H) 2.80-2.90 (m, 2H) 3.00-3.13 (m, 2H) 3.44-3.53 (m, 2H) 3.57-3.68 (m,2H) 6.65 (d, J=9 Hz, 1H) 7.06 (d, J=9 Hz, 1H) 7.46 (dd, J=9, 4 Hz, 1H)7.74 (dd, J=9, 3 Hz, 1H) 8.03 (d, J=5 Hz, 1H) 8.26 (d, J=3 Hz, 1H). MS(DCl/NH₃) m/z 298 (M+H)⁺.

Example 156A5-(6-Chloro-pyridin-3-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

The product of Example 6C (5 g, 23.6 mmol), 5-bromo-2-chloropyridine(Aldrich, 5.02 g, 28.3 mmol), tris(dibenzylideneacetone)dipalladium (0)(Pd₂(dba)₃, Strem, 0.43 g, 0.47 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, Strem, 0.59 g, 0.94mmol) and tert-BuONa (3.63 g, 37.8 mmol) in 50 mL toluene was warmed to85° C. and allowed to stir for 20 h. The mixture was cooled to ambienttemperature, filtered and concentrated under reduced pressure. The crudematerial was purified by column chromatography (SiO₂, 50% hexanes-EtOAc)to give 3.86 g of the title compound (12 mmol, 42% yield) as the majorproduct. MS (DCl/NH₃) m/z 324 (M+H)⁺.

Examples 156-187

The product of Example 156A was coupled with the indicated boronic acid,and processed according to the methods listed in the table below.

Example Boronic Acid Conditions Resulting Compound 156 Phenyl boronicacid 1) H 2-(6-Phenyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole bis-2) FB trifluoroacetate ¹H NMR (300 MHz, CD₃OD) δ ppm 3.32 (m, 4H), 3) S43.62 (m, 6H), 7.57 (m, 3H), 7.68 (dd, J = 9.2, 2.7 Hz, 1H), 7.81 (m,2H), 8.01 (m, 2H) MS (DCI/NH₃) m/z 266 (M + H)⁺; Anal. calculated forC₁₇H₁₉N₃•2CF₃CO₂H: C, 51.12; H, 4.29; N, 8.52. Found: C, 51.12; H, 4.12;N, 8.37. 157 3-Biphenyl boronic 1) G2-(6-Biphenyl-3-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4- acid 2) FBc]pyrrole trifluoroacetate 3) S4 ¹H NMR (CH₃OH-d₄, 300 MHz) δ 3.33 (m,4H), 3.63 (m, 6H), 7.39 (m, 1H), 7.48 (m, 2H), 7.67 (m, 4H), 7.79 (m,2H), 8.07 (m, 3H); MS (DCI/NH₃) m/z 342 (M + H)⁺; Anal. calculated forC₂₃H₂₃N₃•2CF₃CO₂H: C, 56.94; H, 4.42; N, 7.38. Found: C, 56.64; H, 4.39;N, 7.09. 158 o-tolyl boronic acid 1) H2-(6-o-Tolyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole bis- 2) FBtrifluoroacetate ¹H NMR (300 MHz, CD₃OD) δ ppm 2.30 (s, 3H), 3) S4 3.30(m, 3H), 3.35 (m, 1H), 3.62 (m, 6H), 7.41 (m, 4H), 7.70 (m, 2H), 8.05(m, J = 2.7 Hz, 1H); MS (DCI/NH₃) m/z 280 (M + H)⁺; Anal. calculated forC₁₈H₂₁N₃•2.1CF₃CO₂H: C, 51.39; H, 4.49; N, 8.10. Found: C, 51.56; H,4.43; N, 8.11. 159 m-tolyl boronic acid 1) I2-(6-m-Tolyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole 2) FBbis-trifluoroacetate ¹H NMR (300 MHz, CD₃OD) δ ppm 2.45 (s, 3H), 3) S43.26 (m, 2H), 3.36 (m, 2H), 3.63 (m, 6H), 7.36 (m, 1H), 7.45 (t, J = 7.5Hz, 1H), 7.61 (m, 2H), 7.67 (dd, J = 9.2, 3.1 Hz, 1H), 7.99 (dd, J =5.9, 2.9 Hz, 2H); MS (DCI/NH₃) m/z 280 (M + H)⁺; Anal. calculated forC₁₈H₂₁N₃•2CF₃CO₂H: C, 52.09; H, 4.59; N, 8.28. Found: C, 52.10; H, 4.44;N, 8.23. 160 m-(trifluoro- 1) I2-[6-(3-Trifluoromethyl-phenyl)-pyridin-3-yl]-octahydro- methyl)phenyl2) FB pyrrolo[3,4-c]pyrrole trifluoroacetate boronic acid 3) S4 ¹H NMR(CH₃OH-d₄, 300 MHz) δ 3.28 (m, 4H), 3.56 (m, 6H), 7.37 (dd, J = 8.8, 3.1Hz, 1H), 7.67 (m, 2H), 7.87 (d, J = 8.8 Hz, 1H), 8.10 (m, 2H), 8.18 (m,1H); MS (DCI/NH₃) m/z 334 (M + H)⁺; Anal. C₁₈H₁₈F₃N₃•1.6CF₃CO₂H: C, H,N. 161 m-tolyl boronic acid 1) G2-[6-(3-Methoxy-phenyl)-pyridin-3-yl]-octahydro-pyrrolo[3,4- 2) FBc]pyrrole bis-trifluoroacetate ¹H NMR (300 MHz, CD₃OD) δ ppm 3) S4 3.28(m, 2H), 3.35 (m, 2H), 3.62 (m, 6H), 3.89 (s, 3H), 7.10 (m, 1H), 7.37(m, 2H), 7.47 (t, J = 8.1 Hz, 1H), 7.66 (dd, J = 9.2, 2.7 Hz, 1H), 8.00(dd, J = 6.1, 2.7 Hz, 2H); MS (DCI/NH₃) m/z 296 (M + H)⁺; Anal.calculated for C₁₈H₂₁N₃O•2 CF₃CO₂H: C, 50.48; H, 4.43; N, 8.03. Found:C, 50.68; H, 4.51; N, 8.09. 162 3-trifluoromethoxy- 1) G2-[6-(3-Trifluoromethoxy-phenyl)-pyridin-3-yl]-octahydro- phenyl boronicacid 2) FB pyrrolo[3,4-c]pyrrole trifluoroacetate ¹H NMR (300 MHz,CD₃OD) δ 3) S4 ppm 3.26 (m, 2H), 3.34 (m, 2H), 3.56 (m, 6H), 7.31 (m,1H), 7.38 (dd, J = 8.8, 3.1 Hz, 1H), 7.57 (t, J = 8.1 Hz, 1H), 7.79 (s,1H), 7.84 (m, 1H), 7.85 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 3.1 Hz, 1H);MS (DCI/NH₃) m/z 350 (M + H)⁺; Anal. calculated for C₁₈H₁₈N₃F₃O•1.5CF₃CO₂H: C, 47.74; H, 3.72; N, 7.95. Found: C, 47.83; H, 3.60; N, 7.80.163 Thiophen-3-yl 1) G2-(6-Thiophen-3-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4- boronic acid 2)FB c]pyrrole bis-trifluoroacetate ¹H NMR (300 MHz, CD₃OD) δ ppm 3) S43.26 (m, 2H), 3.36 (m, 2H), 3.55 (m, 4H), 3.65 (m, 2H), 7.58 (dd, J =8.8, 3.1 Hz, 1H), 7.62 (m, 2H), 7.94 (m, 1H), 7.96 (s, 1H), 7.99 (dd, J= 2.4, 1.7 Hz, 1H) MS (DCI/NH₃) m/z 272 (M + H)⁺; Anal. calculated forC₁₅H₁₇N₃S•2CF₃CO₂H: C, 45.69; H, 3.83; N, 8.41. Found: C, 46.00; H,3.74; N, 8.51. 165 8-quinoline boronic 1) G8-[5-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-2-yl]- acid 2) FBquinoline tris-trifluoroacetate ¹H NMR (300 MHz, CD₃OD) δ ppm 3) S4 3.30(m, 2H), 3.39 (m, 2H), 3.69 (m, 6H), 7.82 (m, 2H), 7.89 (t, J = 7.8 Hz,1H), 8.23 (d, J = 8.5 Hz, 1H), 8.28 (d, J = 3.1 Hz, 1H), 8.55 (d, J =9.5 Hz, 1H), 8.59 (dd, J = 7.5, 1.0 Hz, 1H), 8.73 (dd, J = 8.5, 1.7 Hz,1H), 9.15 (dd, J = 4.7, 1.7 Hz, 1H); MS (DCI/NH₃) m/z 317 (M + H)⁺;Anal. calculated for C₂₀H₂₀N₄•3CF₃CO₂H: C, 47.43; H, 3.52; N, 8.51.Found: C, 47.67; H, 3.55; N, 8.53. 166 3-aminophenyl 1) G3-[5-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-2-yl]- boronic acid2) FB phenylamine trifluoroacetate 3) S4 ¹H NMR (CH₃OH-d₄, 300 MHz) δ3.27 (m, 1H), 3.34 (m, 3H) 3.57 (m, 4H), 3.64 (m, 2H), 7.07 (ddd, J =7.8, 2.4, 1.7 Hz, 1H), 7.37 (m, 2H), 7.42 (m, 1H), 7.62 (dd, J = 9.1,3.1 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 8.00 (d, J = 2.7 Hz, 1H); MS(DCI/NH₃) m/z 281 (M + H)⁺; Anal. calculated for C₁₇H₂₀N₄•2.7CF₃CO₂H: C,45.74; H, 3.89; N, 9.52. Found: C, 45.86; H, 3.90; N, 9.69. 1672-naphthalene 1) G2-(6-Naphthalen-2-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4- boronic acid2) FB c]pyrrole bis-trifluoroacetate ¹H NMR (300 MHz, CD₃OD) δ ppm 3) S43.30 (m, 2H), 3.37 (m, 2H), 3.64 (m, 6H), 7.59 (m, 2H), 7.70 (dd, J =9.0, 2.9 Hz, 1H), 7.92 (m, 1H), 7.98 (m, 2H), 8.05 (d, J = 5.1 Hz, 1H),8.07 (s, 1H), 8.15 (d, J = 9.2 Hz, 1H), 8.35 (m, 1H); MS (DCI/NH₃) m/z316 (M + H)⁺; Anal. calculated for C₂₁H₂₁N₃•2CF₃CO₂H: C, 55.25; H, 4.27;N, 7.73. Found: C, 55.16; H, 4.23; N, 7.63. 168 2-benzofuran 1) G2-(6-Benzofuran-2-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4- boronic acid2) FB c]pyrrole bis-trifluoroacetate ¹H NMR (300 MHz, CD₃OD) δ ppm 3) S43.31 (m, 4H), 3.58 (m, 6H), 7.30 (m, 4H), 7.54 (d, J = 8.8 Hz, 1H), 7.63(m, 1H), 7.94 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 2.7 Hz, 1H); MS(DCI/NH₃) m/z 306 (M + H)⁺; Anal. calculated for C₁₉H₁₉N₃O•2CF₃CO₂H: C,51.79; H, 3.97; N, 7.88. Found: C, 51.52; H, 3.71; N, 7.69. 169Benzo[b]thiophen-2- 1) I2-(6-Benzo[b]thiophen-2-yl-pyridin-3-yl)-octahydro- yl boronic acid 2)FB pyrrolo[3,4-c]pyrrole trifluoroacetate 3) S4 ¹H NMR (CH₃OH-d₄, 300MHz) δ 3.26 (m, 4H), 3.45 (m, 2H), 3.55 (m, 2H), 3.63 (m, 2H), 7.21 (dd,J = 8.8, 3.1 Hz, 1H), 7.32 (m, 2H), 7.73 (br s, 1H), 7.78 (m, 1H), 7.83(m, 2H), 8.03 (br d, J = 2.7 Hz, 1H); MS (DCI/NH₃) m/z 322 (M + H)⁺;Anal. calculated for C₁₉H₁₉N₃S•1.1CF₃CO₂H: C, 56.98; H, 4.53; N, 9.40.Found: C, 57.11; H, 4.44; N, 9.21. 170 3-furanyl boronic 1) G5-(6-Furan-3-yl-pyridin-3-yl)-hexahydro-pyrrolo[3,4-c]pyrrole acid 2) FBtrifluoroacetate 3) S4 ¹H NMR (CH₃OH-d₄, 300 MHz) δ 3.25 (m, 2H), 3.33(m, 2H), 3.55 (m, 4H), 3.64 (m, 2H), 6.97 (dd, J = 2.0, 1.0 Hz, 1H),7.60 (dd, J = 9.2, 3.1 Hz, 1H), 7.70 (dd, J = 1.7, 1.7 Hz, 1H), 7.87 (d,J = 9.2 Hz, 1H), 7.91 (d, J = 2.7 Hz, 1H), 8.19 (dd, J = 1.4, 1.0 Hz,1H). MS (DCI/NH₃) m/z 256 (M + H)⁺; Anal. calculated forC₁₅H₁₇N₃O•2CF₃CO₂H: C, 47.21; H, 3.96; N, 8.69. Found: C, 47.17; H,4.01; N, 8.65 171 3-Biphenyl boronic 1) G2-(6-Biphenyl-3-yl-pyridin-3-yl)-5-methyl-octahydro- acid 2) FBpyrrolo[3,4-c]pyrrole p-toluenesulfonate 3) RA ¹H NMR (CH₃OH-d₄, 300MHz) δ 2.34 (s, 3H), 2.96 (s, 3H), 3.35 (m, 6H), 4) S1 3.62 (m, 4H),7.21 (m, 2H), 7.36 (m, 2H), 7.46 (m, 2H), 7.53 (m, 1H), 7.63 (ddd, J =7.8, 1.7, 1.0 Hz, 1H), 7.69 (m, 4H), 7.81 (ddd, J = 7.8, 1.7, 1.0 Hz,1H) 7.82 (m, 1H), 8.10 (dd, J = 2.0, 1.4 Hz, 1H), 8.15 (br d, J = 2.7Hz, 1H); MS (DCI/NH₃) m/z 356 (M + H)⁺; Anal. calculated forC₂₄H₂₅N₃•C₇H₈O₃S•0.5H₂O: C, 69.38; H, 6.39; N, 7.83. Found: C, 69.24; H,6.27; N, 7.78. 172 o-tolyl boronic acid 1) H2-Methyl-5-(6-o-tolyl-pyridin-3-yl)-octahydro-pyrrolo[3,4- 2) FBc]pyrrole bis-L-tartrate 3) S5 ¹H NMR (300 MHz, CD₃OD) δ ppm 2.26 (s,3H), 2.93 (s, 3H), 3.30 (m, 6H), 3.66 (m, 4H), 4.45 (m, 4H), 7.26 (m,4H), 7.34 (m, 2H), 8.11 (m, 1H); MS (DCI/NH₃) m/z 294 (M + H)⁺; Anal.calculated for C₁₉H₂₃N₃•2. C₄H₆O₆: C, 54.08; H, 5.90; N, 6.90. Found: C,53.91; H, 5.72; N, 6.51. 173 m-tolyl boroic acid 1) H2-Methyl-5-(6-m-tolyl-pyridin-3-yl)-octahydro-pyrrolo[3,4- 2) FBc]pyrrole bis-L-tartrate 3) RA ¹H NMR (300 MHz, CD₃OD) δ ppm 1.24 (m,2H), 2.41 (s, 3H), 2.93 (s, 3H), 4) S5 3.31 (m, 4H), 3.62 (d, J = 8.8Hz, 2H), 3.69 (m, 2H), 4.45 (s, 4H), 7.18 (d, J = 7.5 Hz, 1H), 7.31 (m,2H), 7.61 (d, J = 7.8 Hz, 1H), 7.66 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H),8.11 (d, J = 2.7 Hz, 1H); MS (DCI/NH₃) m/z 294 (M + H)⁺; Anal.calculated for C₁₉H₂₃N₃•2.3C₄H₆O₆: C, 53.04; H, 5.81; N, 6.58. Found: C,52.65; H, 6.16; N, 6.28. 174 m-(trifluoro- 1) I2-Methyl-5-[6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]- methyl)phenyl 2)FB octahydro-pyrrolo[3,4-c]pyrrole L-tartrate 3) RA ¹H NMR (CH₃OH-d₄,300 MHz) δ 2.93 (s, 3H), 3.34 (m, 6H) 3.65 (m, 4H), 4) S5 4.44 (s, 4H),7.30 (dd, J = 8.8, 3.1 Hz, 1H), 7.63 (m, 2H), 7.81 (d, J = 8.8 Hz, 1H),8.12 (m, 1H), 8.17 (br d, J = 3.1 Hz, 1H) 8.19 (m, 1H); MS (DCI/NH₃) m/z348 (M + H)⁺; Anal. C₁₉H₂₀F₃N₃•2.1C₄H₆O₆: C, H, N. 175 Phenyl boronicacid 1) G 2-Methyl-5-(6-phenyl-pyridin-3-yl)-octahydro-pyrrolo[3,4- 2)FB c]pyrrole L-tartrate 3) RA ¹H NMR (300 MHz, CD₃OD) δ ppm 2.87 (s,3H), 3.30 (m, 6H), 3.60 (m, 4H), 4) S5 4.40 (s, 2H), 7.29 (dd, J = 8.8,2.7 Hz, 1H), 7.35 (m, 1H), 7.44 (m, 2H), 7.71 (d, J = 8.5 Hz, 1H), 7.83(m, 2H), 8.12 (d, J = 3.1 Hz, 1H); MS (DCI/NH₃) m/z 280 (M + H)⁺; Anal.calculated for C₁₈H₁₈N₃F₃O•1.05 C₄H₆O₆: C, 61.02; H, 6.30; N, 9.62.Found: C, 61.00; H, 5.99; N, 9.46. 176 3-methoxyphenyl 1) G2-[6-(3-Methoxy-phenyl)-pyridin-3-yl]-5-methyl-octahydro- boronic acid2) FB pyrrolo[3,4-c]pyrrole bis-L-tartrate 3) RA ¹H NMR (300 MHz, CD₃OD)δ ppm 2.93 (s, 3H), 3.30 (m, 6H), 3.61 (m, 2H), 4) S5 3.70 (m, 2H), 3.85(m, 3H), 4.44 (m, 4H), 6.92 (m, 1H), 7.32 (m, 4H), 7.71 (d, J = 8.8 Hz,1H), 8.12 (d, J = 3.1 Hz, 1H); MS (DCI/NH₃) m/z 310 (M + H)⁺; Anal.calculated for C₁₉H₂₃N₃O•2.25 C₄H₆O₆•H₂O: C, 50.56; H, 5.83; N, 6.32.Found: C, 50.47; H, 5.92; N, 6.45. 177 3-trifluoromethoxy- 1) G2-Methyl-5-[6-(3-trifluoromethoxy-phenyl)-pyridin-3-yl]-octahydro-phenyl boronic acid 2) FB pyrrolo[3,4-c]pyrrole bis-L-tartrate 3) RA ¹HNMR (300 MHz, CD₃OD) δ ppm 2.93 (s, 3H), 3.33 (m, 6H), 3.63 (d, 4) S5 J= 8.5 Hz, 2H), 3.70 (m, 2H), 4.45 (s, 4H), 7.25 (m, 1H), 7.28 (dd, J =8.8, 3.1 Hz, 1H), 7.52 (t, J = 8.1 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H),7.80 (m, 1H), 7.86 (d, J = 8.1 Hz, 1H), 8.16 (d, J = 3.1 Hz, 1H); MS(DCI/NH₃) m/z 364 (M + H)⁺; Anal. calculated for C₁₉H₂₃N₃O•2 C₄H₆O₆: C,48.87; H, 4.86; N, 6.33. Found: C, 48.54; H, 4.89; N, 6.22. 1783-nitrophenyl 1) G2-Methyl-5-[6-(3-nitro-phenyl)-pyridin-3-yl]-octahydro-pyrrolo[3,4-c]pyrroleboronic acid 2) FB p-toluenesulfonate 3) RA ¹H NMR (300 MHz, CD₃OD) δppm 2.35 (s, 3H), 2.94 (s, 3H), 3.26 (m, 3H), 4) S1 3.43 (m, 3H), 3.68(m, 3H), 3.99 (m, 1H), 7.22 (m, 2H), 7.33 (m, 1H), 7.69 (m, 3H), 7.88(d, J = 8.8 Hz, 1H), 8.21 (m, 2H), 8.28 (m, 1H), 8.77 (dd, J = 1.9, 1.9Hz, 1H); MS (DCI/NH₃) m/z 325 (M + H)⁺; Anal. calculated forC₁₈H₂₀N₄O₂•C₇H₈O₃S•H₂O: C, 58.35; H, 5.88; N, 10.89. Found: C, 58.19; H,5.64; N, 10.64. 179 Thiophen-3-yl 1) G2-Methyl-5-(6-thiophen-3-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrolep- boronic acid 2) FB toluenesulfonate 3) RA ¹H NMR (300 MHz, CD₃OD) δppm 2.36 (s, 3H), 2.93 (s, 3H), 3.30 (m, 6H), 4) S1 3.59 (m, 4H), 7.22(d, J = 7.8 Hz, 2H), 7.27 (dd, J = 8.8, 3.1 Hz, 1H), 7.47 (dd, J = 5.1,3.1 Hz, 1H), 7.58 (dd, J = 5.1, 1.4 Hz, 1H), 7.68 (m, 3H), 7.77 (dd, J =2.9, 1.2 Hz, 1H), 8.05 (d, J = 2.7 Hz, 1H); MS (DCI/NH₃) m/z 286 (M +H)⁺; Anal. calculated for C₁₆H₁₉N₃S•C₇H₈O₃S: C, 60.37; H, 5.95; N, 9.18.Found: C, 60.12; H, 5.92; N, 9.03. 181 8-quinoline boronic 1) G8-[5-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-2-yl]-quinolinep- acid 2) FB toluenesulfonate 3) RA ¹H NMR (300 MHz, CD₃OD) δ ppm 2.35(s, 3H), 2.93 (s, 3H), 3.33 (m, 6H), 4) S1 3.61 (m, 4H), 7.22 (d, J =7.8 Hz, 2H), 7.37 (dd, J = 8.6, 2.9 Hz, 1H), 7.57 (dd, J = 8.3, 4.2 Hz,1H), 7.71 (m, 3H), 7.86 (d, J = 8.8 Hz, 1H), 7.98 (ddd, J = 14.1, 7.6,1.4 Hz, 2H), 8.19 (d, J = 2.7 Hz, 1H), 8.42 (dd, J = 8.5, 1.7 Hz, 1H),8.87 (dd, J = 4.2, 1.9 Hz, 1H); MS (DCI/NH₃) m/z 331 (M + H)⁺; Anal.calculated for C₂₁H₂₂N₄•C₇H₈O₃S: C, 66.91; H, 6.02; N, 11.15. Found: C,66.80; H, 5.91; N, 11.14. 182 2-naphthalene 1) G2-Methyl-5-(6-naphthalen-2-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrroleboronic acid 2) FB p-toluenesulfonate 3) RA ¹H NMR (300 MHz, CD₃OD) δppm 2.35 (s, 3H), 2.95 (s, 3H), 3.34 (m, 6H), 4) S1 3.64 (m, 4H), 7.22(m, 2H), 7.34 (dd, J = 8.8, 2.7 Hz, 1H), 7.50 (m, 2H), 7.70 (m, 2H),7.90 (m, 4H), 8.02 (dd, J = 8.5, 1.7 Hz, 1H), 8.18 (d, J = 2.7 Hz, 1H),8.32 (m, 1H); MS (DCI/NH₃) m/z 330 (M + H)⁺; Anal. calculated forC₂₂H₂₃N₃•C₇H₈O₃S: C, 69.43; H, 6.23; N, 8.38. Found: C, 69.06; H, 5.86;N, 8.05. 183 Benzo[b]thiophen-2- 1) I2-(6-Benzo[b]thiophen-2-yl-pyridin-3-yl)-5-methyl-octahydro- yl boronicacid 2) FB pyrrolo[3,4-c]pyrrole p-toluenesulfonate 3) RA ¹H NMR(CH₃OH-d₄, 300 MHz) δ 2.36 (s, 3H), 2.93 and 2.98 (rotamer s, 4) S4 3H),3.27 (m, 2H), 3.29 (m, 2H), 3.42 (m, 2H), 3.65 (m, 3H), 3.98 (m, 1H),7.22 (m, 2H), 7.32 (m, 3H), 7.70 (m, 2H), 7.75 (br s, 1H), 7.78 (m, 1H),7.84 (dd, J = 7.1, 2.0 Hz, 1H), 7.85 (br d, J = 8.5 Hz, 1H), 8.07 (br d,J = 2.4 Hz, 1H); MS (DCI/NH₃) m/z 322 (M + H)⁺; Anal. calculated forC₂₀H₂₁N₃S•1.2C₇H₈O₃S•H₂O: C, 60.90; H, 5.87; N, 7.50. Found: C, 60.93;H, 5.74; N, 7.31. 184 3-furanyl boronic 1) G2-(6-Furan-3-yl-pyridin-3-yl)-5-methyl-octahydro-pyrrolo[3,4- acid 2) FBc]pyrrole p-toluenesulfonate 3) RA ¹H NMR (CH₃OH-d₄, 300 MHz) δ 2.35 (s,4H) 2.95 (m, 4H), 3.29 (m, 3H), 4) S1 3.42 (m, 3H), 3.64 (m, 3H), 6.93(dd, J = 2.0, 1.0 Hz, 1H), 7.21 (m, 3H), 7.47 (m, 1H), 7.64 (dd, J =1.7, 1.7 Hz, 1H), 7.68 (m, 3H), 7.72 (m, 1H), 7.97 (m, 1H), 8.11 (dd, J= 1.4, 1.0 Hz, 1H). MS (DCI/NH₃) m/z 270 (M + H)⁺; Anal. calculated forC₁₅H₁₇N₃O•1.5C₇H₈O₂S: C, 60.32; H, 5.92; N, 7.96. Found: C, 60.34; H,6.00; N, 8.11.

Examples 185-187

The product of Example 156 was processed according to the method EC toafford2-(6-chloropyridin-3-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole, whichwas coupled with the specified boronic acid and converted to the titlesalts according to the methods listed in the table.

Example Boronic Acid Conditions Resulting Compound 185 5-indolyl boronicacid 1) I 5-[5-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- 2) S2pyridin-2-yl]-1H-indole Trifluoroacetate ¹H NMR (CH₃OH-d₄, 300 MHz) δppm 2.97 (s, 3H), 3.33-3.83 (m, 10H), 6.62 (d, J = 3.1 Hz, 1H), 7.40 (d,J = 3.1 Hz, 1H), 7.54 (dd, J = 8.7, 1.6 Hz, 1H), 7.61 (d, J = 8.7 Hz,1H), 7.86 (dd, J = 9.0, 2.2 Hz, 1H), 7.93 (s, 1H), 8.05 (s, 1H), 8.12(d, J = 9.4 Hz, 1H); MS (DCI/NH₃) m/z 319 (M + H)⁺; Anal.C₂₀H₂₂N₄•2.1C₂F₃HO₂: C, H, N. 186 4-indolyl boronic acid 1) I4-[5-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- 2) S2pyridin-2-yl]-1H-indole Trifluoroacetate ¹H NMR (CH₃OH-d₄, 300 MHz) δppm 2.98 (s, 3H), 3.13-4.11 (m, 10H), 6.65 (dd, J = 3.2, 0.8 Hz, 1H),7.27-7.37 (m, J = 3.7, 3.7 Hz, 2H), 7.44-7.50 (m, 1H), 7.58-7.67 (m,1H), 7.82-7.93 (m, 1H), 8.06 (s, 1H), 8.14 (d, J = 9.2 Hz, 1H); MS(DCI/NH₃) m/z 319 (M + H)⁺; Anal. C₂₀H₂₂N₄•2C₂F₃HO₂: C, H, N. 1875-quinoline boronic 1) I5-[5-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- acid 2) S3pyridin-2-yl]-quinoline Hydrochloride ¹H NMR (CH₃OH-d₄, 300 MHz) δ ppm3.00 (d, J = 12.2 Hz, 3H), 3.03-3.41 (m, 2H), 3.41-3.82 (m, 8H), 4.03(dd, J = 12.0, 7.3 Hz, 1H), 7.68-7.77 (m, 1H), 7.93 (dd, J = 8.8, 1.7Hz, 1H), 7.97-8.09 (m, 2H), 8.17-8.25 (m, 1H), 8.26-8.37 (m, 2H), 9.10(d, J = 8.8 Hz, 1H), 9.21 (d, J = 5.1 Hz, 1H); MS (DCI/NH₃) m/z 331 (M +H)⁺; Anal. C₂₁H₂₂N₄•3.5HCl•C₂H₆O: C, H, N.

Example 1886a-Methyl-5-(6-m-tolyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-b]pyrrolefumarate

The diamine from Example 20G was coupled to 5-bromo-2-chloropyridineaccording to the procedure of Example 156A. The product was in turncoupled with m-tolyl boronic acid according to the procedure of methodG, and further processed according to methods PD and S2 to provide thetitle compound: ¹H NMR (MeOH-d₄, 300 MHz) δ 1.66 (s, 3H), 2.06-2.13 (m,1H), 2.40 (s, 3H), 2.44-2.54 (m, 1H), 2.84-2.93 (m, 1H), 3.35-3.62 (m,4H), 4.00 (d, J=11.2 Hz, 1H), 6.69 (s, 2.2H), 7.19-7.34 (m, 3H),7.59-7.72 (m, 3H), 8.09 (d, J=2.4 Hz, 1H); MS (DCl/NH₃) m/z 294 (M+H)⁺;Anal. C₁₉H₂₃N₃.1.1C₄H₄O₄: C, H, N.

Examples 191-197

The product of Example 10 was reacted with 3,6-dichloropyridazineaccording to the procedure of Example 90, and the material was in turncoupled to the boronic acid and processed further according to theconditions listed in the table below:

Example Boronic Acid Conditions Resulting Compound 191 p-tolyl boronicacid 1) H (1R,5R)-3-(6-p-Tolyl-pyridazin-3-yl)-3,6-diaza- 2) FBbicyclo[3.2.0]heptane bis(p-toluenesulfonate) 3) S1 ¹H NMR (MeOH-D₄, 300MHz) δ 2.32 (s, 6H), 2.45 (s, 3H), 3.38-3.99 (m, 4H), 4.28-4.40 (m, 2H),4.56 (d, J = 13.6 Hz, 1H), 5.03-5.34 (m, 1H), 7.19 (d, J = 7.8 Hz, 4H),7.44 (m, 2H) 7.66 (d, J = 8.1 Hz, 4H) 7.76-8.00 (m, 3H) 8.37 (d, J = 9.8Hz, 1H); MS (DCI/NH₃) m/z 267 (M + H)⁺; Anal. Calculated forC₁₆H₁₈N₄•2.00C7H8SO3: C, 59.00; H, 5.61; N, 9.17. Found: C, 58.92; H,5.54; N, 9.08. 192 o-tolyl boronic acid 1) H(1R,5R)-3-(6-o-Tolyl-pyridazin-3-yl)-3,6-diaza- 2) FBbicyclo[3.2.0]heptane bis(p-toluenesulfonate) 3) S1 ¹H NMR (MeOH-D₄, 300MHz) δ 2.35 (s, 6H), 2.39 (s, 3H), 3.54-3.80 (m, 3H), 3.84 (dd, J =11.0, 5.3 Hz, 1H), 4.17-4.43 (m, 2H), 4.56 (d, J = 13.9 Hz, 1H), 5.19(t, J = 6.1 Hz, 1H), 7.22 (d, J = 8.1 Hz, 4H) 7.33-7.59 (m, 2H) 7.68 (d,J = 8.1 Hz, 4H), 7.92 (d, J = 9.5 Hz, 1H), 8.11 (d, J = 9.5 Hz, 1H); MS(DCI/NH₃) m/z 267 (M + H)⁺; Anal. Calculated forC₁₆H₁₈N₄•2.00C₇H₈SO₃•1.00H₂O: C, 57.31; H, 5.77; N, 8.91. Found: C,57.90; H, 5.60; N, 8.79. 193 m-tolyl boronic acid 1) H(1R,5R)-3-(6-m-Tolyl-pyridazin-3-yl)-3,6-diaza- 2) FBbicyclo[3.2.0]heptane bis(p-toluenesulfonate) 3) S1 ¹H NMR (MeOH-D₄, 300MHz) δ 2.32 (s, 6H), 2.48 (s, 3H), 3.58-3.99 (m, 4H), 4.20-4.40 (m, 2H),4.58 (d, J = 13.6 Hz, 1H), 5.22 (t, J = 6.3 Hz, 1H), 7.19 (d, J = 8.1Hz, 4H), 7.39-7.58 (m, 2H) 7.66 (d, J = 8.1 Hz, 4H), 7.70-7.86 (m, 2H)7.94 (d, J = 9.8 Hz, 1H), 8.40 (d, J = 9.5 Hz, 1H); MS (DCI/NH₃) m/z 267(M + H)⁺; Anal. Calculated for C₁₆H₁₈N₄•2.10C₇H₈SO₃•1.40H₂O: C, 56.35;H, 5.79; N, 8.47. Found: C, 56.60; H, 5.78; N, 8.13. 1943,4-methylenedioxy- 1) H(1R,5R)-3-(6-Benzo[1,3]dioxol-5-yl-pyridazin-3-yl)- benzeneboronic 2) FB3,6-diazabicyclo[3.2.0]heptane bis(p-toluenesulfonate) acid 3) S1 ¹H NMR(MeOH-D₄, 300 MHz) δ 2.33 (s, 6H), 3.55-3.70 (m, 2H), 3.78 (dd, J =12.1, 5.8 Hz, 1H), 3.88 (dd, J = 11.9, 5.1 Hz, 1H), 4.20-4.36 (m, 2H),4.56 (d, J = 12.9 Hz, 1H), 5.21 (t, J = 5.8 Hz, 1H), 6.11 (s, 2H), 7.04(d, J = 8.2 Hz, 1H), 7.20 (d, J = 8.1 Hz, 4H), 7.46-7.52 (m, 2H), 7.65(d, J = 8.4 Hz, 4H), 7.88 (d, J = 9.9 Hz, 1H), 8.33 (d, J = 9.8 Hz, 1H);MS (DCI/NH₃) m/z 297 (M + H)⁺; Anal. Calculated forC₁₆H₁₆N₄O₂•2.00C₇H₈SO₃: C, 56.24; H, 5.03; N, 8.74. Found: C, 56.01; H,4.94; N, 8.51. 195 p-tolyl boronic acid 1) H(1R,5R)-6-Methyl-3-(6-p-tolyl-pyridazin-3-yl)-3,6- 2) FBdiaza-bicyclo[3.2.0]heptane fumarate 3) RA ¹H NMR (MeOH-D₄, 300 MHz) δ2.40 (s, 3H), 2.89 (s, 3H), 4) S1 3.31-3.66 (m, 3H), 3.91 (dd, J = 10.7,4.6 Hz, 1H), 4.10-4.18 (m, 2H), 4.50 (d, J = 13.6 Hz, 1H), 4.68-4.97 (m,1H), 6.68 (s, 2H), 7.18-7.44 (m, 3H), 7.84 (d, J = 8.5 Hz, 2H), 7.95 (d,J = 9.5 Hz, 1H); MS (DCI/NH₃) m/z 281 (M + H)⁺; Anal. Calculated forC₁₇H₂₀N₄•1.10C₄H₄O₄•0.50H₂O: C, 61.90; H, 6.12; N, 13.49. Found: C,61.97; H, 5.77; N, 13.72. 196 o-tolyl boronic acid 1) H(1R,5R)-6-Methyl-3-(6-o-tolyl-pyridazin-3-yl)-3,6- 2) FBdiaza-bicyclo[3.2.0]heptane bis(p-toluenesulfonate) 3) RA ¹H NMR(MeOH-D₄, 300 MHz) δ 2.35 (s, 6H), 2.38 (s, 3H), 4) S1 3.05 (s, 3H),3.58-3.85 (m, 3H) 4.20 (d, J = 6.4 Hz, 2H), 4.30 (d, J = 10.5 Hz, 1H),4.64 (d, J = 14.6 Hz, 1H) 4.98-5.18 (m, 1H), 7.21 (d, J = 7.8 Hz, 4H),7.35-7.59 (m, 4H), 7.68 (d, J = 8.1 Hz, 4H) 7.95 (d, J = 9.8 Hz, 1H)8.15 (d, J = 9.8 Hz, 1H); MS (DCI/NH₃) m/z 281 (M + H)⁺; Anal.Calculated for C₁₇H₂₀N₄•2.10C₇H₈SO₃•1.00H₂O: C, 57.69; H, 5.93; N, 8.49.Found: C, 57.50; H, 5.60; N, 8.79. 197 3,4-methylenedioxy 1) H(1R,5R)-3-(6-Benzo[1,3]dioxol-5-yl-pyridazin-3-yl)-6- benzeneboronic 2)FB methyl-3,6-diaza-bicyclo[3.2.0]heptane bis(p- acid 3) RAtoluenesulfonate) 4) S1 ¹H NMR (MeOH-D₄, 300 MHz) δ 2.31 (s, 6H), 3.04(s, 3H), 3.52-3.79 (m, 3H), 4.05-4.38 (m, 3H), 4.61 (d, J = 13.9 Hz,2H), 5.07 (t, J = 6.3 Hz, 1H), 6.10 (s, 2H), 7.03 (d, J = 7.8 Hz, 1H),7.18 (d, J = 7.8 Hz, 4H), 7.35-7.56 (m, 2H), 7.64 (d, J = 8.1 Hz, 4H),7.75 (d, J = 9.5 Hz, 1H), 8.22 (d, J = 9.8 Hz, 1H); MS (DCI/NH₃) m/z 311(M + H)⁺; Anal. Calculated for C₁₇H₁₈N₄O₂•2.10C₇H₈SO₃•1.00H₂O: C, 56.87;H, 5.23; N, 8.56. Found: C, 56.85; H, 5.37; N, 8.74.

Examples 204-208

The product of Example 8B was reacted with 3,6-dichloropyridazineaccording to the procedure of Example 90, and the material was in turncoupled to the boronic acid and processed further according to theconditions listed in the table below:

Example Boronic Acid Conditions Resulting Compound 204 5-indolylboronic 1) MW (1S,5S)-5-[6-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)- acid 2)FB pyridazin-3-yl]-1H-indole Fumarate 3) S2 ¹H NMR (CH₃OH-d₄, 300 MHz) δppm 3.29-3.38 (m, 1H), 3.45 (dd, J = 13.6, 5.1 Hz, 1H), 3.51-3.65 (m,1H), 3.78 (dd, J = 11.4, 5.3 Hz, 1H), 4.17 (d, J = 11.2 Hz, 1H), 4.30(dd, J = 11.0, 8.6 Hz, 1H), 4.48 (d, J = 13.6 Hz, 1H), 5.10 (dd, J =7.1, 5.1 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 6.71 (s, 2H), 7.30 (d, J =3.4 Hz, 1H), 7.34 (d, J = 9.5 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.75(dd, J = 8.5, 1.7 Hz, 1H), 8.02 (d, J = 9.5 Hz, 1H), 8.13 (s, 1H); MS(APCI/NH₃) m/z 292 (M + H)⁺; Anal. C₁₇H₁₇N₅•1.5C₄H₄O₄•0.5H₂O: C, H, N.205 5-indolyl boronic 1) MW(1S,5S)-5-[6-(6-Methyl-3,6-diaza-bicyclo[3.2.0]hept-3- acid 2) RAyl)-pyridazin-3-yl]-1H-indole Bis(trifluoroacetate) 3) S4 ¹H NMR(CH₃OH-d₄, 300 MHz) δ ppm 3.02 (s, 3H), 3.43-3.72 (m, 4H), 4.07-4.29 (m,2H), 4.53-4.66 (m, 1H), 5.03 (s, 1H), 6.64 (d, J = 4.1 Hz, 1H), 7.39 (d,J = 3.4 Hz, 1H), 7.57-7.64 (m, 1H), 7.67-7.73 (m, 1H), 7.78 (d, J = 9.8Hz, 1H), 8.20 (d, J = 1.4 Hz, 1H), 8.39 (d, J = 9.8 Hz, 1H); MS(DCI/NH₃) m/z 306 (M + H)⁺; Anal. C₁₈H₁₉N₅•2C₂F₃HO₂: C, H, N. 2064-indolyl boronic 1) MW(1S,5S)-4-[6-(6-Methyl-3,6-diaza-bicyclo[3.2.0]hept-3- acid 2) S4yl)-pyridazin-3-yl]-1H-indole Bis(trifluoroacetate) ¹H NMR (CH₃OH-d₄,300 MHz) δ ppm 3.03 (s, 3H), 3.45-3.73 (m, 4H), 4.09-4.30 (m, 2H), 4.63(d, J = 12.9 Hz, 1H), 5.04 (s, 1H), 6.81 (dd, J = 3.4, 1.0 Hz, 1H), 7.32(t, J = 7.8 Hz, 1H), 7.43-7.49 (m, 2H), 7.63 (d, J = 7.8 Hz, 1H), 7.75(d, J = 9.5 Hz, 1H), 8.33 (d, J = 9.5 Hz, 1H); MS (DCI/NH₃) m/z 306 (M +H)⁺; Anal. C₁₈H₁₉N₅•2.5C₂F₃HO₂: C, H, N. 207 5-(4,4,5,5- 1) MW(1S,5S)-3-(6-Benzofuran-5-yl-pyridazin-3-yl)-6- tetramethyl-1,3,2- 2) S4methyl-3,6-diaza-bicyclo[3.2.0]heptane dioxaborolan-2-yl)-Bis(trifluoroacetate) 1-benzofuran ¹H NMR (CH₃OH-d₄, 300 MHz) δ ppm 3.03(s, 3H), 3.46-3.72 (m, 4H), 4.09-4.29 (m, J = 16.3 Hz, 2H), 4.56-4.68(m, 1H), 5.04 (s, 1H), 6.99 (dd, J = 2.4, 1.0 Hz, 2H), 7.68 (d, J = 5.4Hz, 1H), 7.71 (d, J = 4.4 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.93 (dd, J= 8.8, 2.0 Hz, 1H), 8.24 (d, J = 1.7 Hz, 1H), 8.30 (d, J = 9.5 Hz, 1H);MS (DCI/NH₃) m/z 307 (M + H)⁺; Anal. C₁₈H₁₈N₄O•2.5C₂F₃HO₂: C, H, N. 208p-aminobenzene 1) I (1S,5S)-4-[6-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)-boronic acid 2) FB pyridazin-3-yl]-phenylamine tri(p-toluenesulfonate)3) S1 ¹H NMR (MeOH-D₄, 300 MHz) δ 2.33 (s, 9H), 3.76-4.05 (m, 4H),4.20-4.40 (m, 2H), 4.58 (d, J = 1 3.9 Hz, 1H) 5.22 (t, J = 5.9 Hz, 1H)7.20 (d, J = 8.5 Hz, 6H) 7.36 (d, J = 8.5 Hz, 2H) 7.67 (d, J = 8.1 Hz,6H) 7.91 (d, J = 9.8 Hz, 1H) 8.01 (d, J = 8.8 Hz, 2H) 8.37 (d, J = 9.8Hz, 1H); MS (DCI/NH₃) m/z 268 (M + H)⁺; Anal. Calculated forC₁₅H₁₇N₅•3.23C₇H₈SO₃•0.50H₂O: C, 54.26; H, 5.31; N, 8.41. Found: C,53.93; H, 4.82; N, 8.02.

Example 209-211

The product of Example 7J was reacted with 3,6-dichloropyridazineaccording to the procedure of Example 90, and subjected to N-methylationaccording to method EC. The material was in turn coupled to the boronicacid and processed further according to the conditions listed in thetable below:

Example Boronic Acid Conditions Resulting Compound 209 3-thienylboronic 1) MW (1R,5S)-3-[6-(3-Methyl-3,6-diaza-bicyclo[3.2.0]hept-6-acid 2) S4 yl)-pyridazin-3-yl]-thiophene trifluroacetate ¹H NMR(CH₃OH-d₄, 300 MHz) δ ppm 3.08 (s, 3H), 3.19-3.38 (m, 2H), 3.51-3.61 (m,1H), 3.91 (dd, J = 8.6, 3.2 Hz, 1H), 4.02 (dd, J = 25.1, 12.2 Hz, 2H),4.30 (t, J = 8.3 Hz, 1H), 5.23 (dd, J = 6.6, 3.6 Hz, 1H), 7.01 (d, J =9.2 Hz, 1H), 7.54 (dd, J = 5.1, 2.7 Hz, 1H), 7.71 (dd, J = 5.1, 1.4 Hz,1H), 7.92 (d, J = 9.5 Hz, 1H), 7.96 (dd, J = 3.1, 1.4 Hz, 1H); MS(DCI/NH₃) m/z 273 (M + H)⁺; Anal. C₁₄H₁₆N₄S•1.3C₂F₃HO₂•0.8H₂O: C, H, N.210 5-indolyl boronic acid 1) I(1R,5S)-5-[6-(3-Methyl-3,6-diaza-bicyclo[3.2.0]hept-6- 2) FByl)-pyridazin-3-yl]-1H-indole bis(trifluroacetate) 3) S1 ¹H NMR(MeOH-D₄, 300 MHz) δ 3.05 (s, 3H), 3.50-3.61 (m, 1H), 3.88-4.08 (m, 4H)4.13 (d, J = 12.9 Hz, 1H), 4.40 (t, J = 8.5 Hz, 1H), 5.30 (dd, J = 6.8,3.7 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 7.24-7.43 (m, 2H) 7.55-(d, J =8.8 Hz, 1H), 7.70 (dd, J = 8.5, 1.7 Hz, 1H), 8.14 (d, J = 1.7 Hz, 1H),8.23 (d, J = 9.5 Hz, 1H); MS (DCI/NH₃) m/z 306 (M + H)⁺; Anal.Calculated for C₁₈H₁₉N₅•2.00CF₈CO₂H•0.50H₂O: C, 50.09; H, 4.47; N,12.43. Found: C, 49.97; H, 4.04; N, 12.07. 211 4-indolyl boronic acid 1)MW (1R,5S)-4-[6-(3-Methyl-3,6-diaza-bicyclo[3.2.0]hept-6- 2) S4yl-pyridazin-3-yl]-1H-indole bis(trifluroacetate) ¹H NMR (CH₃OH-d₄, 300MHz) δ ppm 3.10 (s, 3H), 3.30-3.41 (m, 2H), 3.60-3.72 (m, 1H), 3.99-4.09(m, 2H), 4.18 (d, J = 12.9 Hz, 1H), 4.45 (t, J = 8.6 Hz, 1H), 5.36 (dd,J = 6.8, 4.1 Hz, 1H), 6.83 (dd, J = 3.2, 0.8 Hz, 1H), 7.25-7.32 (m, 1H),7.39-7.46 (m, 3H), 7.60 (d, J = 8.1 Hz, 1H), 8.26 (d, J = 9.5 Hz, 1H);MS (DCI/NH₃) m/z 306 (M + H)⁺; Anal. C₁₈H₁₉N₅•2.4C₂F₃HO₂•0.8H₂O: C, H,N.

Example 2123-Methyl-5-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-1H-indazolebis(trifluoroacetate) Example 212A3-Methyl-5-trimethylstannanyl-indazole-1-carboxylic acid tert-butylester

Hexamethylditin (4.73 g, 14.4 mmol) was added to a mixture of3-methyl-5-bromo-indazole-1-carboxylic acid tert-butyl ester (3.0 g, 9.6mmol) and Pd(PPh₃)₄ (1.1 g, 0.96 mmol) in toluene (50 mL). The solutionwas purged with nitrogen, and heated to 115° C. under nitrogen for 2 h.The black reaction mixture was cooled to room temperature, loaded onto acolumn of silica gel and eluted with EtOAc-Hexane (5-30%) to provide thetitle compound (3.06 g, 80% yield): MS (DCl/NH₃) m/z 396 (M+H)⁺.

Example 212B3-Methyl-5-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-1H-indazolebis(trifluoroacetate)

The product of Example 114 (120 mg, 0.5 mmol) was combined with theproduct of Example 212A (278 mg, 0.7 mmol). Dioxane (10 mL),tris(dibenzylidene)-dipalladium (Pd₂(dba)₃, 24 mg, 0.025 mmol), Pd(Pbu^(t) ₃, 26 mg, 0.05 mmol) and CsF (152 mg, 1 mmol) were added, andthe mixture was stirred at 100° C. under nitrogen for 16 h. The reactionwas cooled to room temperature, diluted with ethyl acetate (30 mL) andwashed with water. The organic phase was concentrated under vacuum, andthe residue was purified by column chromatography (10% MeOH—CH₂Cl₂) toprovide the free base (120 mg, 55% yield) which was converted to thetitle compound by method S4: ¹H NMR (300 MHz, CH₃OH-d₄) δ 2.63 (s, 3H),2.99 (s, 3H), 3.23-4.07 (m, 10H), 7.58-7.70 (m, J=8.6, 8.6 Hz, 2H), 8.03(dd, J=8.8, 1.4 Hz, 1H), 8.36 (s, 1H), 8.42 ppm (d, J=9.8 Hz, 1H); MS(DCl/NH₃) m/z 335 (M+H)⁺; Anal. calculated for C₁₉H₂₂N₆.2.28C₂F₃HO₂: C,47.61; H, 4.12; N, 14.14. Found: C, 47.26; H, 3.92; N, 14.44.

Example 213(1S,5S)-5-[6-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-3-yl]-3-methyl-1H-indazoletri(p-toluenesulfonate)

The product of Example 9 was reacted with 2,5-dibromopyridine accordingto the procedure of Example 128A, then coupled with the product ofExample 212A according to the procedure of Example 212B. The resultingproduct was deprotected according to procedure FB and converted to thesalt by method S4 to provide the title compound: ¹H NMR (MeOH-D₄, 300MHz) δ 2.32 (s, 9H), 2.65 (s, 3H) 3.67-3.73 (m, 2H), 3.82 (dd, J=13.2,5.8 Hz, 1H), 3.90 (dd, J=11.2, 4.1 Hz, 1H), 4.25-4.37 (m, 2H), 4.58 (d,J=13.2 Hz, 1H), 5.24 (t, J=6.1 Hz, 1H), 7.20 (d, J=7.8 Hz, 6H), 7.41 (d,J=9.2 Hz, 1H), 7.64-7.70 (d, J=7.8 Hz, 6H), 7.72-7.75 (dd, J=8.8, 1.2Hz, 1H), 7.80 (dd, J=8.8, 1.6 Hz, 1H), 8.16 (m, 1H), 8.26 (d, J=1.7 Hz,1H), 8.46 (dd, J=9.5, 2.4 Hz, 1H); MS (DCl/NH₃) m/z 306 (M+H)⁺; Anal.Calculated for C₁₈H₁₉N₅.3.30C₇H₈SO₃.1.50H₂O: C, 54.81; H, 5.42; N, 7.78.Found: C, 54.98; H, 5.30; N, 7.40.

Example 224(1R,5S)-3-Phenyl-6-(6-phenyl-pyridazin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptanebis(p-toluenesulfonate)

The diamine from Example 9 was coupled with 3-chloro-6-phenylpyridazineaccording to the procedure of Method A. The product was deprotected bythe procedure of Method PD, then coupled with bromobenzene according tothe general procedure of Example 156A. The product was then converted tothe salt with p-toluenesulfonic acid according to Method S1 to providethe title compound: ¹H NMR (CD₃OD, 300 MHz) δ 2.40 (s, 6H), 2.99-3.22(m, 2H), 3.57-3.76 (m, 1H), 3.99 (d, J=10.5 Hz, 1H), 4.13-4.27 (m, 2H),4.48-4.64 (m, 1H), 5.30-5.47 (m, 1H), 6.89 (t, J=7.3 Hz, 1H), 7.00 (d,J=8.1 Hz, 2H), 7.12-7.36 (m, 7H), 7.46-7.62 (m, 3H), 7.69 (d, J=8.5 Hz,4H), 7.88-8.06 (m, 2H), 8.33 (d, J=9.8 Hz, 1H); MS (DCl/NH₃) m/z 329(M+H)⁺; Anal. Calculated for C₂₁H₂₀N₄.2.00C₇H₈SO₃.1.50H₂O: C, 60.07; H,5.62; N, 8.01. Found: C, 59.97; H, 5.55; N, 7.92.

Examples 225-239

The product of Example 10 was reacted with 5-bromo-2-chloropyridineaccording to the procedure of Example 156A, then coupled with the listedboronic acid and processed according to the procedures indicated in thetable below.

Example Boronic Acid Conditions Resulting Compound 225 4-acetylphenylboronic 1. G (1R,5R)-1-{4-[5-(3,6-Diaza-bicyclo[3.2.0]hept-3- acid 2. FByl)-pyridin-2-yl]-phenyl}-ethanone p- 3. S1 toluenesulfonate ¹H NMR(CH₃OH-d₄, 300 MHz) δ 2.35 (s, 6H), 2.67 (s, 3H), 3.43 (dd, J₁ = 12.9Hz, J₂ = 5.4 Hz, 1H), 3.55-3.67 (m, 1H), 4.09 (d, J = 11.2 Hz, 1H),4.26-4.37 (m, 2H), 5.14 (t, J = 6.5 Hz, 1H), 7.21 (d, J = 7.8 Hz, 4H),7.68 (d, J = 8.1 Hz, 4H), 7.95-8.01 (m, 3H), 8.17-8.22 (m, 3H), 8.28 (d,J = 3.1 Hz, 1H); MS (DCI/NH₃) m/z 294 (M + H)⁺; Anal.C₁₈H₁₉N₃O•2C₇H₈O₃S: C, H, N. 226 4-N,N- 1. G(1R,5R)-{4-[5-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)- dimethylaminophenyl2. FB pyridin-2-yl]-phenyl}-dimethyl-amine p-toluenesulfonate boronicacid 3. S1 ¹H NMR (CH₃OH-d₄, 300 MHz) δ ppm 2.34 (s, 6H), 3.10 (s, 6H),3.23 (dd, J = 10.5, 6.4 Hz, 1H), 3.31-3.39 (m, 1H), 3.51-3.64 (m, 1H),3.79 (dd, J = 11.0, 5.3 Hz, 1H), 4.01 (d, J = 10.9 Hz, 1H), 4.21-4.35(m, 2H), 5.12 (dd, J = 6.8, 5.4 Hz, 1H), 6.94 (d, J = 9.2 Hz, 2H), 7.21(d, J = 8.1 Hz, 4H), 7.69 (d, J = 8.5 Hz, 4H), 7.73 (d, J = 9.2 Hz, 2H),7.97-8.13 (m, 3H); MS (DCI/NH₃) m/z 295 (M + H)⁺; Anal.C₁₈H₂₂N₄•2.4C₇H₈O₃S•0.3H₂O: C, H, N. 227 m-tolyl boronic acid 1. G(1R,5R)-6-Methyl-3-(6-m-tolyl-pyridin-3-yl)-3,6- 2. FBdiaza-bicyclo[3.2.0]heptane p-toluenesulfonate 3. RA ¹H NMR (CH₃OH-d₄,300 MHz) δ ppm 2.33 (s, 6H), 2.48 (s, 3H), 4. S1 3.04 (s, 3H), 3.32-3.38(m, 1H), 3.42 (dd, J = 12.9, 4.7 Hz, 1H), 3.57-3.69 (m, 1H), 4.08 (d, J= 10.8 Hz, 1H), 4.13-4.21 (m, 2H), 4.39 (d, J = 12.9 Hz, 1H), 5.01 (dd,J = 7.3, 4.6 Hz, 1H), 7.20 (d, J = 7.8 Hz, 4H), 7.42-7.56 (m, 2H),7.58-7.71 (m, 6H), 7.99-8.06 (m, 1H), 8.10-8.21 (m, 2H); MS (DCI/NH₃)m/z 280 (M + H)⁺; Anal. C₁₈H₂₁N₃•2C₇H₈O₃S: C, H, N. 228 p-tolyl boronicacid 1. G (1R,5R)-6-Methyl-3-(6-p-tolyl-pyridin-3-yl)-3,6- 2. FBdiaza-bicyclo[3.2.0]heptane p-toluenesulfonate 3. RA ¹H NMR (CH₃OH-d₄,300 MHz) δ ppm 2.34 (s, 6H), 2.46 (s, 3H), 4. S1 3.04 (s, 3H), 3.31-3.36(m, 1H), 3.40 (dd, J = 13.2, 4.7 Hz, 1H), 3.56-3.68 (m, 1H), 4.07 (d, J= 10.8 Hz, 1H), 4.11-4.21 (m, 2H), 4.37 (d, J = 12.9 Hz, 1H), 5.01 (dd,J = 7.3, 4.6 Hz, 1H), 7.20 (d, J = 7.8 Hz, 4H), 7.46 (d, J = 7.8 Hz,2H), 7.67 (d, J = 8.1 Hz, 4H), 7.70-7.76 (m, 2H), 7.99-8.05 (m, 1H),8.09-8.18 (m, 2H); MS (DCI/NH₃) m/z 280 (M + H)⁺; Anal.C₁₈H₂₁N₃•2.25C₇H₈O₃S: C, H, N. 229 m-Cyanophenyl boronic 1. G(1R,5R)-3-[5-(6-Methyl-3,6-diaza- acid 2. FBbicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-benzonitrile p- 3. RAtoluenesulfonate 4. S1 ¹H NMR (CH₃OH-d₄, 300 MHz) δ ppm 2.35 (s, 6H),3.03 (s, 3H), 3.31-3.37 (m, 1H), 3.42 (dd, J = 13.1, 4.9 Hz, 1H),3.56-3.68 (m, 1H), 4.09 (d, J = 10.9 Hz, 1H), 4.13-4.21 (m, 2H), 4.39(d, J = 12.9 Hz, 1H), 5.01 (dd, J = 7.1, 4.7 Hz, 1H), 7.21 (d, J = 8.1Hz, 4H), 7.68 (d, J = 8.1 Hz, 4H), 7.78 (t, J = 8.0 Hz, 1H), 7.90-7.97(m, 2H), 8.10-8.18 (m, J = 9.2 Hz, 2H), 8.22-8.27 (m, 1H), 8.30 (d, J =3.1 Hz, 1H); MS (DCI/NH₃) m/z 291 (M + H)⁺; Anal. C₁₈H₁₈N₄•2.5C₇H₈O₃S:C, H, N. 230 4-ethylphenyl boronic 1. G(1R,5R)-3-[6-(4-Ethyl-phenyl)-pyridin-3-yl]-6- acid 2. FBmethyl-3,6-diaza-bicyclo[3.2.0]heptane p- 3. RA toluenesulfonate 4. S1¹H NMR (CH₃OH-d₄, 300 MHz) δ ppm 1.29 (t, J = 7.6 Hz, 3H), 2.34 (s, 6H),2.77 (q, J = 7.1 Hz, 2H), 3.04 (s, 3H), 3.31-3.36 (m, 1H), 3.40 (dd, J =13.2, 5.1 Hz, 1H), 3.57-3.68 (m, 1H), 4.07 (d, J = 10.8 Hz, 1H),4.11-4.20 (m, 2H), 4.36 (d, J = 12.9 Hz, 1H), 5.01 (dd, J = 7.6, 4.9 Hz,1H), 7.21 (d, J = 7.8 Hz, 4H), 7.48 (d, J = 8.8 Hz, 1H), 7.67 (d, J =8.1 Hz, 4H), 7.75 (d, J = 8.5 Hz, 2H), 7.99-8.05 (m, 1H), 8.11-8.18 (m,2H); MS (DCI/NH₃) m/z 294 (M + H)⁺; Anal. C₁₉H₂₃N₃•2C₇H₈O₃S•0.7H₂O: C,H, N. 231 4-acetylphenyl boronic 1. G(1R,5R)-1-{4-[5-(6-Methyl-3,6-diaza- acid 2. FBbicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-phenyl}- 3. RA ethanonep-toluenesulfonate 4. S1 ¹H NMR (CH₃OH-d₄, 300 MHz) δ 2.33 (s, 6H), 2.67(s, 3H), 3.04 (s, 3H), 3.33-3.50 (m, 2H), 3.57-3.70 (m, 1H), 4.05-4.22(m, 3H), 4.41 (d, J = 12.9 Hz, 1H), 5.02 (t, J = 4.7 Hz, 1H), 7.21 (d, J= 8.1 Hz, 4H), 7.67 (d, J = 8.1 Hz, 4H), 7.92-8.05 (m, 3H), 8.15-8.30(m, 4H); MS (DCI/NH₃) m/z 308 (M + H)⁺; Anal. C₁₉H₂₁N₃O•2C₇H₈O₃S: C, H,N. 232 4-N,N- 1. G (1R,5R)-Dimethyl-{4-[5-(6-methyl-3,6-diaza-dimethylaminophenyl 2. FBbicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-phenyl}- boronic acid 3. RA aminep-toluenesulfonate 4. S1 ¹H NMR (CH₃OH-d₄, 300 MHz) δ ppm 2.34 (s, 6H),3.03 (s, 3H), 3.10 (s, 6H), 3.21-3.39 (m, 2H), 3.53-3.67 (m, 1H), 4.02(d, J = 10.8 Hz, 1H), 4.11-4.20 (m, 2H), 4.32 (d, J = 12.9 Hz, 1H), 4.99(dd, J = 7.0, 4.6 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 7.8Hz, 4H), 7.63-7.77 (m, 6H), 7.94-8.13 (m, 3H); MS (DCI/NH₃) m/z 309 (M +H)⁺; Anal. C₁₉H₂₄N₄•2.3C₇H₈O₃S: C, H, N. 233 m-methoxylphenyl 1. G(1R,5R)-3-[6-(3-Methoxy-phenyl)-pyridin-3-yl]-6- boronic acid 2. FBmethyl-3,6-diaza-bicyclo[3.2.0]heptane fumarate 3. RA ¹H NMR (CH₃OH-d₄,300 MHz) δ ppm 2.96 (s, 3H), 3.08 (dd, 4. S2 J = 10.2, 6.4 Hz, 1H), 3.16(dd, J = 12.9, 4.4 Hz, 1H), 3.47-3.59 (m, 1H), 3.86 (s, 3H), 3.97 (d, J= 10.5 Hz, 1H), 3.97-4.04 (m, 1H), 4.16-4.27 (m, 1H), 4.26 (d, J = 12.9Hz, 1H), 4.94 (dd, J = 7.0, 4.9 Hz, 1H), 6.72 (s, 4H), 6.92-6.97 (m,1H), 7.32-7.39 (m, 1H), 7.41-7.47 (m, 3H), 7.78 (dd, J = 8.8, 0.7 Hz,1H), 8.27 (d, J = 2.4 Hz, 1H); MS (DCI/NH₃) m/z 296 (M + H)⁺; Anal.Calculated for C₁₉H₂₃N₃•2.3C₄H₄O₄: C, H, N. 234 3,4- 1. G(1R,5R)-3-(6-Benzo[1,3]dioxol-5-yl-pyridin-3-yl)- methylenedioxybenzene2. FB 6-methyl-3,6-diaza-bicyclo[3.2.0]heptane boronic acid 3. RAfumarate 4. S2 ¹H NMR (CH₃OH-d₄, 300 MHz) δ ppm 2.90 (s, 3H), 3.03-3.16(m, 2H), 3.45-3.55 (m, 1H), 3.87-3.97 (m, 2H), 4.08-4.18 (m, 1H), 4.19(d, J = 12.9 Hz, 1H), 5.99 (s, 2H), 6.68 (s, 2H), 6.90 (d, J = 8.8 Hz,1H), 7.34-7.44 (m, 3H), 7.69 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 3.1 Hz,1H); MS (DCI/NH₃) m/z 310 (M + H)⁺; Anal. Calculated forC₁₈H₁₉N₃O₂•1.1C₄H₄O₄: C, H, N. 235 4-methoxybenzene 1. G(1R,5R)-3-[6-(4-Methoxy-phenyl)-pyridin-3-yl]-6- boronic acid 2. FBmethyl-3,6-diaza-bicyclo[3.2.0]heptane Fumarate 3. RA ¹H NMR (CH₃OH-d₄,300 MHz) δ ppm 2.91 (s, 3H), 4. S2 3.03-3.16 (m, 2H), 3.45-3.56 (m, J =13.6 Hz, 1H), 3.84 (s, 3H), 3.89-3.97 (m, 2H), 4.09-4.24 (m, J = 12.0,12.0 Hz, 2H), 6.68 (s, 2H), 7.00 (d, J = 9.2 Hz, 2H), 7.42 (dd, J = 8.6,2.9 Hz, 1H), 7.71 (dd, J = 8.8, 0.7 Hz, 1H), 7.80 (d, J = 9.2 Hz, 2H),8.22 (d, J = 2.4 Hz, 1H); MS (DCI/NH₃) m/z 296 (M + H)⁺; Anal.Calculated for C₁₈H₂₁N₃O•1.1C₄H₄O₄: C, H, N. 236 3,4-dimethoxybenzen 1.G (1R,5R)-3-[6-(3,4-Dimethoxy-phenyl)-pyridin-3- boronic acid 2. FByl]-6-methyl-3,6-diaza-bicyclo[3.2.0]heptane 3. RA Fumarate 4. S2 ¹H NMR(CH₃OH-d₄, 300 MHz) δ ppm 2.99 (s, 2H), 3.09 (s, 1H), 3.19 dd, J = 13.1,4.9 Hz, 1H), 3.54-3.64 (m, 1H), 3.91 (s, 3H), 3.95 (s, 3H), 3.95-4.01(m, 1H), 4.25-4.35 (m, 1H), 4.93-5.06 (m, 1H), 6.73 (s, 4H), 7.10 (d, J= 8.5 Hz, 1H), 7.45 (dd, J = 8.5, 2.0 Hz, 1H), 7.48-7.56 (m, 2H), 7.79(d, J = 9.2 Hz, 1H), 8.25 (d, J = 2.7 Hz, 1H); MS (DCI/NH₃) m/z 326 (M +H)⁺; Anal. Calculated for C₁₉H₂₃N₃O₂•1.8C₄H₄O₄: C, H, N. 237 Phenylboronic acid 1. G (1R,5R)-6-Methyl-3-(6-phenyl-pyridin-3-yl)-3,6- 2. FBdiaza-bicyclo[3.2.0]heptane Fumarate 3. RA ¹H NMR (CH₃OH-d₄, 300 MHz) δppm 2.91 (s, 3H), 4. S2 3.05-3.19 (m, 2H), 3.45-3.56 (m, 1H), 3.89-3.98(m, 2H), 4.15 (dd, J = 10.9, 8.8 Hz, 1H), 4.23 (d, J = 12.9 Hz, 1H),4.85-4.90 (m, 1H), 6.68 (s, 2H), 7.32-7.50 (m, 5H), 7.77 (d, J = 8.8 Hz,1H), 7.83-7.90 (m, 2H), 8.27 (d, J = 2.7 Hz, 1H); MS (DCI/NH₃) m/z 266(M + H)⁺; Anal. Calculated for C₁₇H₁₉N₃•1.4C₄H₄O₄: C, H, N. 238Pyridine-3-boronic acid 1. G(1R,5R)-5-(6-Methyl-3,6-diaza-bicyclo[3.2.0]hept- 2. FB3-yl)-[2,3′]bipyridinyl Fumarate 3. RA ¹H NMR (CH₃OH-d₄, 300 MHz) δ ppm2.91 (s, 3H), 4. S2 3.09-3.23 (m, 2H), 3.46-3.57 (m, 1H), 3.89-4.01 (m,2H), 4.09-4.19 (m, 1H), 4.24 (d, J = 12.9 Hz, 1H), 4.85-4.90 (m, 1H),6.69 (s, 2H), 7.45 (dd, J = 8.6, 2.9 Hz, 1H), 7.52 (ddd, J = 8.1, 4.8,0.7 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 8.32-8.39 (m, 2H), 8.52 (dd, J =4.9, 1.5 Hz, 1H), 9.09 (dd, J = 2.4, 0.7 Hz, 1H); MS (DCI/NH₃) m/z 267(M + H)⁺; Anal. Calculated for C₁₆H₁₈N₄•1.2C₄H₄O₄: C, H, N. 2395-indolyl boronic acid 1) I (1R,5R)-5-[5-(6-Methyl-3,6-diaza- 2) FBbicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-1H-indole p- 3) S1toluenesulfonate ¹H NMR (MeOH-D₄, 300 MHz) δ 2.34 (s, 3H), 2.97 (s, 3H),3.07 (dd, J = 10.3, 6.3 Hz, 1H), 3.15 (dd, J = 12.7, 4.6 Hz, 1H),3.41-3.69 (m, 1H), 3.96 (d, J = 10.5 Hz, 1H), 4.26 (d, J = 12.5 Hz, 1H),4.90-5.02 (m, 1H), 6.53 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 8.1 Hz, 2H),7.29 (d, J = 3.4 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.53 (dd, J = 8.8,2.7 Hz, 1H), 7.63 (dd, J = 8.5, 1.7 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H),7.82 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 1.4 Hz, 1H), 8.22 (d, J = 2.7 Hz,1H); MS (DCI/NH₃) m/z 305 (M + H)⁺; Anal. Calculated forC₁₉H₂₀N₄•1.07C₇H₈SO₃•0.50H₂O: C, 62.92; H, 5.89; N, 11.08. Found: C,63.13; H, 5.87; N, 10.70.

Example 240

The product of Example 10 was reacted with 5-bromo-2-chloropyridineaccording to the procedure of Example 156A, then coupled with the listedboronic acid and processed according to the procedures indicated in thetable below.

Example Boronic Acid Conditions Resulting Compound 240 5-indolylboronic 1) I (1S,5S)-5-[5-(6-Methyl-3,6-diaza-bicyclo[3.2.0]hept-3- acid2) FB yl)-pyridin-2-yl]-1H-indole p-toluenesulfonate 3) S1 ¹H NMR(MeOH-D₄, 300 MHz) δ 2.34 (s, 3H), 2.97 (s, 3H), 3.07 (dd, J = 10.3, 6.3Hz, 1H), 3.15 (dd, J = 12.7, 4.6 Hz, 1H), 3.41-3.69 (m, 1H), 3.96 (d, J= 10.5 Hz, 1H), 4.26 (d, J = 12.5 Hz, 1H), 4.90-5.02 (m, 1H), 6.53 (d, J= 2.4 Hz, 1H), 7.21 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 3.4 Hz, 1H), 7.48(d, J = 8.5 Hz, 1H), 7.53 (dd, J = 8.8, 2.7 Hz, 1H), 7.63 (dd, J = 8.5,1.7 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.82 (d, J = 8.8 Hz, 1H), 8.05(d, J = 1.4 Hz, 1H), 8.22 (d, J = 2.7 Hz, 1H); MS (DCI/NH₃) m/z 305 (M +H)⁺; Anal. Calculated for C₁₉H₂₀N₄•1.12C₇H₈SO₃•1.00H₂O: C, 62.56; H,6.06; N, 10.87. Found: C, 62.75; H, 5.75; N, 10.48.

Examples 243-246

The product of Example 8B was reacted with 5-bromo-2-chloropyridineaccording to the procedure of Example 156A, then coupled with the listedboronic acid and processed according to the procedures indicated in thetable below.

Example Boronic Acid Conditions Resulting Compound 243 Phenylboronicacid 1) H (1R,5S)-6-(6-Phenyl-pyridin-3-yl)-3,6-diaza- 2) Pdbicyclo[3.2.0]heptane fumarate 3) S2 ¹H NMR (MeOH-D₄, 300 MHz) δ 3.20(dd, J = 12.5, 3.4 Hz, 1H), 3.32-3.39 (m, 1H), 3.39-3.54 (m, 1H)3.67-3.80 (m, 2H), 3.82 (dd, J = 7.8, 2.7 Hz, 1H), 4.07 (t, J = 7.8 Hz,1H), 4.89-5.03 (m, 1H), 6.68 (s, 2H) 7.10 (dd, J = 8.6, 2.9 Hz, 1H) 7.34(t, J = 7.3 Hz, 1H) 7.39-7.48 (m, 2H), 7.70 (d, J = 8.5 Hz, 1H),7.78-7.86 (m, 2H), 7.92 (d, J = 2.7 Hz, 1H); MS (DCI/NH₃) m/z 252 (M +H)⁺; Anal. Calculated for C₁₉H₂₀N₄•1.00C₄H₄O₄•0.10H₂O: C, 65.06; H,5.79; N, 11.38. Found: C, 64.79; H, 5.42; N, 11.24. 244 m-tolyl boronicacid 1) H (1R,5S)-6-(6-m-Tolyl-pyridin-3-yl)-3,6-diaza- 2) Pdbicyclo[3.2.0]heptane fumarate 3) S2 ¹H NMR (MeOH-D₄, 300 MHz) δ 2.40(s, 3H), 3.18 (dd, J = 12.5, 3.4 Hz, 1H), 3.35 (d, J = 7.5 Hz, 1H),3.38-3.52 (m, 1H), 3.73 (dd, J = 12.2, 9.8 Hz, 2H), 3.81 (dd, J = 8.0,2.9 Hz, 1H), 4.02-4.12 (m, 1H), 4.94 (dd, J = 6.4, 3.4 Hz, 1H), 6.68 (s,2H), 7.09 (dd, J = 8.6, 2.9 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 7.31 (t,J = 7.6 Hz, 1H), 7.55-7.66 (m, 2H), 7.68 (d, J = 8.1 Hz, 1H), 7.91 (d, J= 2.4 Hz, 1H); MS (DCI/NH₃) m/z 266 (M + H)⁺; Anal. Calculated forC₁₇H₁₉N₃•1.00C₄H₄O₄•0.10H₂O: C, 65.06; H, 5.79; N, 11.38. Found: C,64.79; H, 5.42; N, 11.24. 245 Phenylboronic acid 1) H(1R,5S)-3-Methyl-6-(6-phenyl-pyridin-3-yl)-3,6- 2) FBdiaza-bicyclo[3.2.0]heptane fumarate 3) RA ¹H NMR (MeOH-D₄, 300 MHz) δ2.99 (s, 3H), 3.06 (dd, 4) S2 J = 11.9, 3.4 Hz, 1H), 3.16 (dd, J = 12.0,7.3 Hz, 1H), 3.40-3.56 (m, 1H), 3.80-3.88 (m, 2H), 3.91 (d, J = 11.9 Hz,1H), 4.07 (t, J = 8.0 Hz, 1H), 4.93 (dd, J = 6.4, 3.4 Hz, 1H), 6.69 (s,2H) 7.09 (dd, J = 8.6, 2.9 Hz, 2H) 7.29-7.38 (m, 1H) 7.38-7.50 (m, 2H)7.70 (d, J = 8.1 Hz, 2H) 7.77-7.86 (m, 2H) 7.92 (d, J = 2.7 Hz, 1H); MS(DCI/NH₃) m/z 266 (M + H)⁺; Anal. Calculated forC₁₇H₁₉N₃•1.00C₄H₄O₄•0.60H₂O: C, 64.31; H, 6.22; N, 10.71. Found: C,64.11; H, 5.86; N, 10.81. 246 5-indolyl boronic acid 1) I(1R,5S)-5-[5-(3-Methyl-3,6-diaza- 2) FBbicyclo[3.2.0]hept-6-yl)-pyridin-2-yl]-1H-indole 3) RA fumarate 4) S1 ¹HNMR (MeOH-D₄, 300 MHz) δ 2.99 (s, 3H) 3.05 (dd, J = 12.0, 3.2 Hz, 1H),3.15 (dd, J = 12.0, 7.6 Hz, 1H), 3.39-3.58 (m, 1H), 3.77-3.97 (m, 3H)4.06 (t, J = 8.3 Hz, 1H), 4.91 (dd, J = 7.0, 2.9 Hz, 1H), 6.50 (d, J =3.1 Hz, 1H), 6.69 (s, 2.6H), 7.10 (dd, J = 8.6, 2.9 Hz, 1H), 7.26 (d, J= 3.4 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 8.5, 1.7 Hz, 1H),7.70 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 2.7 Hz, 1H), 7.99 (s, 1H); MS(DCI/NH₃) m/z 305 (M + H)⁺; Anal. Calculated forC₁₉H₂₀N₄•1.30C₄H₄O₄•1.00H₂O•1.00C₃H₈O: C, 61.25; H, 6.65; N, 10.50.Found: C, 61.26; H, 6.25; N, 10.86.

Examples 247-250

The product of Example 9 was reacted with 2,5-dibromopyridine accordingto the procedure of Example 128A, then coupled with the listed boronicacid and processed according to the procedures indicated in the tablebelow.

Example Boronic Acid Conditions Resulting Compound 247 5-indolyl boronicacid 1) I (1S,5S)-5-[6-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)- 2) FBpyridin-3-yl]-1H-indole bis(p-toluenesulfonate) 3) S1 ¹H NMR (MeOH-D₄,300 MHz) δ 2.29 (s, 1H), 3.59-3.88 (m, 4H), 4.23 (d, J = 9.9 Hz, 1H),4.33 (dd, J = 11.2, 8.8 Hz, 1H), 4.50 (d, J = 13.2 Hz, 1H), 5.22 (t, J =6.1 Hz, 1H), 6.55 (d, J = 3.1 Hz, 1H), 7.20 (t, J = 8.1 Hz, 4H),7.29-7.43 (m, 3H), 7.53 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 8.1 Hz, 4H),7.83 (d, J = 1.7 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 8.30-8.52 (m, 1H);MS (DCI/NH₃) m/z 291 (M + H)⁺; Anal. Calculated forC₁₈H₁₈N₄•2.00C₇H₈SO₃•1.50H₂O: C, 58.76; H, 6.44; N, 7.61. Found: C,58.58; H, 6.12; N, 7.50. 248 Phenylboronic acid 1) H(1S,5S)-3-(5-Phenyl-pyridin-2-yl)-3,6-diaza- 2) FB bicyclo[3.2.0]heptanebis(p-toluenesulfonate) 3) S1 ¹H NMR (MeOH-D₄, 300 MHz) δ 2.38 (s, 6H),3.61-3.75 (m, 2H), 3.79 (dd, J = 13.6, 5.8 Hz, 1H), 3.88 (dd, J = 11.5,4.7 Hz, 1H), 4.24 (d, J = 10.2 Hz, 1H), 4.27-4.39 (m, 1H), 4.51 (d, J =13.2 Hz, 1H), 5.22 (t, J = 6.1 Hz, 1H), 7.20 (d, J = 7.8 Hz, 4H), 7.37(d, J = 9.5 Hz, 1H), 7.42-7.58 (m, 2H), 7.59-7.78 (m, 7H), 8.16 (d, J =1.7 Hz, 1H), 8.37 (dd, J = 9.5, 2.4 Hz, 1H); MS (DCI/NH₃) m/z 252 (M +H)⁺; Anal. Calculated for C₁₆H₁₇N₃•2.10C₇H₈SO₃•0.50H₂O: C, 59.29; H,5.64; N, 6.76. Found: C, 58.94; H, 5.87; N, 6.51. 249 Phenylboronicacid 1) H (1S,5S)-6-Methyl-3-(5-phenyl-pyridin-2-yl)-3,6- 2) FBdiaza-bicyclo[3.2.0]heptane fumarate 3) RA ¹H NMR (MeOH-D₄, 300 MHz) δ2.93 (s, 3H), 3.16-3.40 (m, 4) S1 2H), 3.40-3.54 (m, 1H) 3.85-3.95 (m,1H) 4.01-4.06 (m, 1H) 4.20 (d, J = 20.3 Hz, 1H) 4.43 (d, J = 13.2 Hz,1H), 4.87-5.00 (m, 1H), 6.70 (s, 2H), 6.93 (d, J = 8.8 Hz, 1H), 7.32 (t,J = 7.1 Hz, 1H), 7.39-7.50 (m, 2H), 7.52-7.66 (m, 2H), 7.93 (dd, J =8.5, 2.4 Hz, 1H), 8.44 (d, J = 2.7 Hz, 1H); MS (DCI/NH₃) m/z 266 (M +H)⁺; Anal. Calculated for C₁₇H₁₉N₃•1.00C₄H₄O₄•0.50H₂O: C, 64.60; H,6.20; N, 10.76. Found: C, 64.96; H, 6.30; N, 10.46. 250 5-indolylboronic acid 1. MW (1S,5S)-5-[6-(6-Methyl-3,6-diaza- 2. ECbicyclo[3.2.0]hept-3-yl)-pyridin-3-yl]-1H-indole 3. S4Bis(trifluoroacetate) ¹H NMR (CH₃OH-d₄, 300 MHz) δ ppm 3.03 (s, 3H),3.40-3.71 (m, 4H), 4.06-4.26 (m, 2H), 4.50 (d, J = 14.6 Hz, 1H), 5.02(s, 1H), 6.52 (dd, J = 3.2, 0.8 Hz, 1H), 7.20 (d, J = 9.2 Hz, 1H), 7.30(d, J = 3.1 Hz, 1H), 7.35 (dd, J = 8.5, 2.0 Hz, 1H), 7.50 (d, J = 8.5Hz, 1H), 7.80 (d, J = 1.0 Hz, 1H), 8.26 (dd, J = 9.0, 2.2 Hz, 1H), 8.34(d, J = 1.7 Hz, 1H); MS (DCI/NH₃) m/z 305 (M + H)⁺; Anal.C₁₉H₂₀N₄•2C₂F₃HO₂•1.25H₂O: C, H, N.

Example 2512-Methyl-5-(3-phenyl-isoxazol-5-yl)-octahydro-pyrrolo[3,4-c]pyrroleExample 251A2-Methyl-5-(3-phenyl-isoxazol-5-yl)-octahydro-pyrrolo[3,4-c]pyrrolefumarate

The product of Example 6C (1 g, 7.9 mmol), and5-chloro-3-phenyl-isoxazole (1.4 g, 7.9 mmol) (prepared according toliterature procedure: Dannhardt, G.; Obergrusberger, I. Chemiker-Zeitung1989, 113, 109-113) in DBU (1.3 g, 8.6 mmol) were warmed to 140-145° C.for 40 min. The reaction mixture was cooled to ambient temperature,CH₂Cl₂ was added, and the crude material was purified by flash columnchromatography (SiO₂, 10% CH₃OH—CH₂Cl₂ with 1% NH₄OH) to provide 0.54 gof the coupled product (2.0 mmol, 25% yield). This was converted to thefumarate salt by method S4 to give 0.65 g of the title compound (1.69mmol, 87% yield). ¹H NMR (CH₃OH-d₄, 300 MHz) δ 2.84 (s, 3H), 3.15-3.32(m, 3H), 3.42-3.62 (m, 7H), 5.62 (s, 1H), 7.42 (m, 3H), 7.65 (m, 2H),8.11; MS (DCl/NH₃) m/z 270 (M+H)⁺; Anal. calculated forC₁₆H₁₉N₃O.C₄H₄O₄: C, 62.33; H, 6.01; N, 10.90. Found: C, 62.23; H, 5.93;N, 10.82.

Example 2522-(3-Phenyl-[1,2,4]thiadiazol-5-yl)-octahydro-pyrrolo[3,4-c]pyrroleExample 252A5-(3-Phenyl-[1,2,4]thiadiazol-5-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

5-Chloro-3-phenyl-[1,2,4]thiadiazole (0.75 g, 3.81 mmol) was preparedaccording to literature procedure (Goerdeler, J. et al Chem. Ber. 1957,90, 182) and was combined with the product of Example 6C (0.85 g, 4.0mmol), tris(dibenzylideneacetone)dipalladium (0) Pd₂(dba)₃, Strem, 0.105g, 0.11 mmol), 1,3-bis(2,6-di-1-propylphenyl)imidazolium chloride(Strem, 97 mg, 0.23 mmol) and tert-BuONa (Aldrich, 0.73 g, 7.6 mmol) in40 mL PhCH₃. This mixture was degassed three times with N₂ backflush.The reaction was warmed to 85° C. for 18 h then was cooled to ambienttemperature, concentrated under reduced pressure and purified via columnchromatography (SiO₂, 50% hexanes-EtOAc) to give 1.02 g of the titlecompound (2.74 mmol, 72% yield). MS (DCl/NH₃) m/z 373 (M+H)⁺.

Example 252B2-(3-Phenyl-[1,2,4]thiadiazol-5-yl)-octahydro-pyrrolo[3,4-c]pyrrolep-toluenesulfonate

The product of Example 252A was processed according to methods FB and S1to provide the title salt: ¹H NMR (CH₃OH-d₄, 300 MHz) δ 2.36 (s, 3H),2.38 (m, 1H), 3.36 (m, 3H), 3.63 (m, 4H), 3.84 (m, 2H), 7.22 (m, 2H),7.43 (m, 3H), 7.70 (m, 2H), 8.14 (m, 2H); MS (DCl/NH₃) m/z 273 (M+H)⁺;Anal. calculated for C₁₄H₁₆N₄S.1.2C₇H₈O₃S: C, 56.17; H, 5.39; N, 11.70.Found: C, 56.28; H, 5.46; N, 11.63.

Example 2532-Methyl-5-(3-phenyl-[1,2,4]thiadiazol-5-yl)-octahydro-pyrrolo[3,4-c]pyrrolefumarate

The product of Example 252A was processed according to method FB, RA,and S4 to provide the title salt: ¹H NMR (CH₃OH-d₄, 300 MHz) δ 2.81 (s,3H), 3.17 (dd, J=11.2, 4.8 Hz, 2H), 3.36 (m, 2H), 3.48 (m, 2H), 3.63(dd, J=11.2, 2.7 Hz, 2H), 3.78 (m, 2H), 6.69 (s, 2H), 7.44 (m, 3H), 8.13(m, 2H); MS (DCl/NH₃) m/z 287 (M+H)⁺; Anal. calculated forC₁₅H₁₈N₄S.C₄H₄O₄: C, 56.70; H, 5.51; N, 13.92. Found: C, 56.42; H, 5.51;N, 13.71.

Example 254 2-(4-Phenyl-thiophen-2-yl)-octahydro-pyrrolo[3,4-c]pyrrolep-toluenesulfonate Example 254A5-(4-Phenyl-thiophen-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

The product of Example 6C (0.75 g, 3.5 mmol) was combined with2-bromo-4-phenyl-thiophene (0.8 g, 3.35 mmol, prepared according toliterature procedure (Gronowitz, S.; Gjös, N.; Kellogg, R. M.; Wynberg,H. J. Org. Chem. 1967, 32, 463-464)),tris(dibenzylideneacetone)dipalladium (0) (Pd₂(dba)₃, Strem, 92 mg, 0.10mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BiNAP,Strem, 0.10 g, 0.17 mmol), and NaOt-Bu (0.64 g, 6.7 mmol) in toluene (40mL). This mixture was placed under vacuum, then purged with N₂ andstirred under nitrogen at 85° C. for 18 h. The reaction mixture wascooled to ambient temperature, filtered through diatomaceous earth andconcentrated under reduced pressure. The residue was purified by columnchromatography (SiO₂, 50% hexanes in EtOAc) to provide the titlecompound (0.39 g, 1.1 mmol, 33% yield). MS (DCl/NH₃) m/z 371 (M+H)⁺.

Example 254B 2-(4-Phenyl-thiophen-2-yl)-octahydro-pyrrolo[3,4-c]pyrrolep-toluenesulfonate

The product of Example 254A was processed according to methods FB and S1to provide the title compound: ¹H NMR (300 MHz, CD₃OD) δ ppm 2.36 (s,3H), 3.24 (m, 6H), 3.41 (m, 2H), 3.57 (m, 2H), 6.41 (d, J=1.7 Hz, 1H),6.84 (d, J=1.7 Hz, 1H), 7.24 (m, 3H), 7.34 (m, 2H), 7.57 (m, 2H), 7.70(m, 2H); MS (DCl/NH₃) m/z 271 (M+H)⁺; Anal. calculated forC₁₆H₁₈N₂S.1.1C₇H₈O₃S: C, 61.91; H, 5.87; N, 6.09. Found: C, 61.78; H,6.14; N, 6.15.

Example 2552-(5-Phenyl-[1,3,4]thiadiazol-2-yl)-octahydro-pyrrolo[3,4-c]pyrroleExample 255A 2-Bromo-5-phenyl-[1,3,4]thiadiazole

A mixture of 2-amino-5-phenyl-1,3,4-thiadiazole sulfate (Aldrich, 2.5 g,9.08 mmol) and 48% aqueous HBr (10 mL) was cooled to 5° C. and asolution of NaNO₂ (0.69 g, 9.99 mmol) H₂O (10 mL) was added dropwise ata rate so the internal temperature is maintained at approximately 5° C.The mixture was stirred for 15 min after the addition, then CuBr (0.69g, 4.8 mmol) was added portion-wise so as to maintain the temperature atapproximately 5° C. After the addition was complete, the mixture wasallowed to warm to ambient temperature and stirred for 16 h. The mixturewas diluted with 20 mL CH₂Cl₂ and 10 mL H₂O. The organic layer wasseparated and concentrated under reduced pressure to provide the titlecompound (1.63 g, 6.76 mmol, 74% yield). MS (DCl/NH₃) m/z 241, 243(M+H)⁺.

Example 255B5-(5-Phenyl-[1,3,4]thiadiazol-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

The products of Examples 6C (0.70 g, 3.32 mmol) and 255A (0.88 g, 3.65mmol) were reacted under the conditions of Example 254A to provide thetitle compound (0.53 g, 1.42 mmol, 43% yield). MS (DCl/NH₃) m/z 373(M+H)⁺.

Example 255C2-(5-Phenyl-[1,3,4]thiadiazol-2-yl)-octahydro-pyrrolo[3,4-c]pyrrolefumarate

The product of Example 255B was processed according to method FB and S4to provide the title salt: ¹H NMR (CH₃OH-d₄, 300 MHz) δ 3.27 (m, 1H),3.33 (m, 3H), 3.60 (m, 4H), 3.79 (m, 2H), 6.68 (s, 2H), 7.46 (m, 3H),7.80 (m, 2H); MS (DCl/NH₃) m/z 305 (M+H)⁺; Anal. calculated forC₁₄H₁₆N₄S.C₄H₄O₄.0.3H₂O: C, 54.89; H, 5.27; N, 14.23. Found: C, 54.66;H, 6.10; N, 14.19.

Example 2562-Methyl-5-(5-phenyl-[1,3,4]thiadiazol-2-yl)-octahydro-pyrrolo[3,4-c]pyrrolebis-p-toluenesulfonate

The product of Example 255B was processed according to methods FB, RA,and S1 to provide the title salt: ¹H NMR (300 MHz, CD₃OD) δ ppm 2.35 (s,6H), 2.97 (s, 3H), 3.09 (m, 2H), 3.48 (m, 2H), 3.70 (m, 4H), 3.91 (m,2H), 7.21 (m, 4H), 7.51 (m, 3H), 7.69 (m, 4H), 7.82 (m, 2H); MS(DCl/NH₃) m/z 287 (M+H)⁺; Anal. calculated forC₁₅H₁₈N₄S.2.1C₇H₈O₃S.0.3H₂O: C, 54.59; H, 5.46; N, 8.57. Found: C,54.24; H, 5.06; N, 8.54.

Example 257 2-(1-Phenyl-1H-pyrazol-4-yl)-octahydro-pyrrolo[3,4-c]pyrroleExample 257A 4-Bromo-1-phenyl-1H-pyrazole

A solution of bromine (1.1 g, 6.94 mmol) in acetic acid (10 mL) wasadded to a mixture of 1-phenylpyrazole (Aldrich, 1 g, 6.94 mmol) inacetic acid (10 mL). This mixture was warmed to 100° C. in a pressuretube for 8 h. The material was cooled to ambient temperature, pouredinto ice and H₂O neutralized with excess saturated, aqueous NaHCO₃.Ethyl acetate (50 mL) was added and the layers were separated. Theaqueous layer was extracted with EtOAc (2×15 mL) and the combinedorganic extract was dried over Na₂SO₄ and concentrated under reducedpressure to give a crude solid. Purification by column chromatography(SiO₂, 50% hexanes-EtOAc) provided the title compound (1.5 g, 6.72 mmol,97% yield). MS (DCl/NH₃) m/z 223, 225 (M+H)⁺.

Example 257B5-(1-Phenyl-1H-pyrazol-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

To the product of Example 6C (0.5 g, 2.4 mmol) in 15 mL toluene in apressure tube was added the product of Example 257A (0.68 g, 3.06 mmol),tris(dibenzylideneacetone)dipalladium (0) (Pd₂(dba)₃, Strem, 43 mg,0.047 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP,Strem, 59 mg, 0.094 mmol), and tert-BuONa (0.362 g, 3.8 mmol). Thismixture was warmed to 85° C. and stirred for 18 h. At this point, thereaction was incomplete, so additional Pd₂(dba)₃ (43 mg, 0.047 mmol) andBINAP (59 mg, 0.094 mmol) were added and the mixture stirred for anadditional 24 h. The reaction was cooled to ambient temperature,filtered through Celite® diatomaceous earth, concentrated under reducedpressure and purified via flash column chromatography (SiO₂, 50%hexanes-EtOAc) to give the title compound (40 mg, 0.113 mmol, 5% yield).MS (DCl/NH₃) m/z 355 (M+H)⁺.

Example 257C2-(1-Phenyl-1H-pyrazol-4-yl)-octahydro-pyrrolo[3,4-c]pyrrolep-toluenesulfonate

The product of Example 257B was processed according to methods FB and S1to provide the title salt: ¹H NMR (CH₃OH-d₄, 300 MHz) δ 2.35 (s, 3H),2.98 (m, 2H), 3.18 (m, 2H), 3.23 (m, 2H), 3.35 (br d, J=9.5 Hz, 2H),3.57 (m, 2H), 7.21 (m, 2H), 7.27 (tt, J=7.1, 1.4 Hz, 1H), 7.45 (m, 3H),7.68 (m, 4H), 7.80 (d, J=0.7 Hz, 1H); MS (DCl/NH₃) m/z 255 (M+H)⁺; Anal.calculated for C₁₅H₁₈N₄.1.1C₇H₈O₃S: C, 61.44; H, 6.09; N, 12.63. Found:C, 61.04; H, 6.09; N, 12.45.

Example 258 2-(5-Phenyl-isoxazol-3-yl)-octahydro-pyrrolo[3,4-c]pyrrolep-toluenesulfonate Example 258A5-(1-Methylsulfanyl-3-oxo-3-phenyl-propenyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

3,3-Bis-methylsulfanyl-1-phenyl-propenone (0.675 g, 3.0 mmol), wasprepared according to literature procedure (Galli, F. et al WO 01/92251A1) and was combined with the product of Example 6C (0.213 g, 1.0 mmol)in 10 mL MeOH. This mixture was warmed to 70° C. for 4 h then was cooledto ambient temperature, concentrated under reduced pressure and purifiedvia column chromatography (SiO₂, 90/10/1 dichloromethane-methanol-NH₄OH)to give 0.169 g of the title compound (0.43 mmol, 43% yield). MS(DCl/NH₃) m/z 389 (M+H)⁺.

Example 258B5-(5-Phenyl-isoxazol-3-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

The product of example 258B (0.163 g, 0.42 mmol), hydroxylaminehydrochloride (0.126 g, 1.7 mmol), sodium acetate (0.13 g, 1.3 mmol)were combined in toluene (4 mL), acetic acid (2 mL), water (0.5 mL), andethanol. The mixture was heated to reflux for 8 h. The mixture waspoured into saturated aqueous sodium carbonate and extracted with EtOAc.The organics were dried over MgSO₄ and concentrated under reducedpressure. The residue was purified by column chromatography (SiO₂, 50%hexanes in EtOAc) to provide the title compound (0.109 g, 0.3 mmol, 71%yield). MS (DCl/NH₃) m/z 356 (M+H)⁺.

Example 258C 2-(5-Phenyl-isoxazol-3-yl)-octahydro-pyrrolo[3,4-c]pyrrolep-toluenesulfonate

The product of Example 258B was processed according to method FB, and S1to provide the title salt: ¹H NMR (300 MHz, CDCl₃) δ 2.24 (s, 3H) 2.92(s, 2H) 3.18 (s, 2H) 3.31 (s, 2H) 3.49 (s, 1H) 3.52 (s, 1H) 3.61-3.75(m, 2H) 6.08 (s, 1H) 7.09 (d, J=8 Hz, 3H) 7.38-7.55 (m, 3H) 7.67 (t, J=7Hz, 3H) 9.27 ppm (s, 1H); MS (DCl/NH₃) m/z 256 (M+H)⁺; Anal. calculatedfor C₁₅H₁₇N₃.1.2C₇H₈O₃S.0.9H₂O: C, 58.78; H, 5.99; N, 8.79. Found: C,59.03; H, 5.73; N, 8.53.

Example 2592-Methyl-5-(5-phenyl-isoxazol-3-yl)-octahydro-pyrrolo[3,4-c]pyrrolep-toluenesulfonate

The product of Example 258C was processed according to method RA, and S1to provide the title salt: 1H NMR (300 MHz) δ 2.23-2.49 (m, 3H)2.87-2.94 (m, 3H) 2.95-3.01 (m, 2H) 3.10-3.72 (m, 8H) 6.48-6.61 (m, 1H)7.13-7.29 (m, 2H) 7.42-7.55 (m, 3H) 7.65-7.74 (m, 2H) 7.72-7.85 ppm (m,2H); MS (DCl/NH₃) m/z 270 (M+H)⁺; Anal. Calculated forC₁₆H₁₉N₅₃O.1.3C₇H₈SO₃C, 61.12; H, 6.01, 8.52. Found: C, 60.92; H, 5.74;N, 8.64

Example 260 2-(5-Phenyl-thiazol-2-yl)-octahydro-pyrrolo[3,4-c]pyrrolep-toluenesulfonate Example 260A5-(5-Bromo-thiazol-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

A solution of Example 6C (1.0 g, 4.2 mmol) in N,N-diisopropylethylamine(1.5 mL, 8.4 mmol) was treated with 2,5-dibromothiazole (0.89 g, 4.2mmol, Aldrich). This mixture was warmed to 110° C. and stirred for 2hours. The reaction mixture was cooled to ambient temperature,concentrated under reduced pressure, and purified by columnchromatography (SiO₂, 20-40% ethyl acetate/hexanes gradient) to afford1.1 g of the title compound (2.9 mmol, 69% yield). ¹H NMR (CDCl₃, 300MHz) δ 1.46 (s, 9H), 2.97-3.09 (m, 2H), 3.21-3.41 (m, 4H), 3.60-3.71 (m,4H), 7.09 (s, 1H); MS (DCl/NH₃) m/z 376 (M+H⁺).

Example 260B5-(5-Phenyl-thiazol-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

The product of Example 260A was coupled with phenylboronic acidaccording to the procedure of method I to provide the title compound: ¹HNMR (CDCl₃, 300 MHz)

1.46 (s, 9H), 3.00-3.17 (m, 2H), 3.24-3.54 (m, 4H), 3.61-3.72 (m, 2H),3.74-3.86 (m, 2H), 7.22 (m, 1H), 7.34 (t, 2H, J=7.6 Hz), 7.42 (d, 3H,J=8.5 Hz); MS (DCl/NH₃) m/z 372 (M+H⁺).

Example 260C 2-(5-Phenyl-thiazol-2-yl)-octahydro-pyrrolo[3,4-c]pyrrolep-toluenesulfonate

The product of Example 260B was processed according to methods FB and S1to provide the title compound: ¹H NMR (MeOH-d₄, 300 MHz)

3.57-3.67 (m, 3H), 3.74-3.84 (m, 2H), 7.22 (d, 2H, J=7.8 Hz), 7.29 (m,1H), 7.35-7.42 (m, 2H), 7.47-7.52 (m, 2H), 7.56 (s, 1H), 7.70 (m, 2H);MS (DCl/NH₃) m/z 272 (M+H⁺).

Example 2612-Methyl-5-(5-phenyl-thiazol-2-yl)-octahydro-pyrrolo[3,4-c]pyrrolep-toluenesulfonate

The product of Example 260B was processed according to methods FB, RAand S1 to provide the title compound: ¹H NMR (MeOH-d₄, 300 MHz)

2.36 (s, 3H), 2.95 (s, 3H), 3.33-3.43 (m, 2H), 3.57-3.65 (m, 4H), 7.24(t, 3H, J=8.0 Hz), 7.35 (t, 2H, J=7.6 Hz), 7.45-7.50 (m, 3H), 7.7 (d,2H, J=8.1 Hz); MS (DCl/NH₃) m/z 286 (M+H⁺). Anal. calculated forC₁₆H₁₉N₃S.C₇H₈O₃S: C, 60.37; H, 5.95; N, 9.18. Found: C, 60.04; H, 6.04;N, 9.15.

Example 262 2-(2-Phenyl-thiazol-5-yl)-octahydro-pyrrolo[3,4-c]pyrroletrifluoroacetate Example 262A 2-Phenylthiazole

A solution of 2-bromothiazole (1.0 g, 6.1 mmol, Aldrich) in dioxane (25mL) was treated with phenylboronic acid (0.82 g, 6.4 mmol),Pd(P^(t)Bu₃)₂ (0.16 g, 0.3 mmol, Strem) and Cs₂CO₃ (3.97 g, 12.2 mmol).The mixture was stirred at 80° C. for 12 hours. The reaction mixture wascooled to ambient temperature, concentrated under reduced pressure, andpurified by column chromatography (SiO₂, 1:1 hexanes/ethyl acetate) togive provide the title compound (0.69 g, 4.3 mmol, 70%). ¹H NMR (CDCl₃,300 MHz)

7.33 (m, 1H), 7.41-7.48 (m, 3H), 7.87 (d, 1H, J=3.4 Hz), 7.95-8.00 (m,2H); MS (DCl/NH₃) m/z 162 (M+H⁺).

Example 262B 5-Bromo-2-phenylthiazole

N-Bromosuccinimide (0.33 g, 1.86 mmol) was added to a solution of theproduct of Example 262A (0.15 g, 0.93 mmol) in N,N-dimethylformamide (5mL). The reaction mixture was stirred at 50° C. for 12 hours. Themixture was then diluted with ethyl acetate (50 mL) and washed withbrine (2×20 mL). The organic layer was dried over magnesium sulfate,concentrated under reduced pressure, and purified by columnchromatography (SiO₂, 20-40% ethyl acetate/hexanes gradient) to providethe title compound (0.20 g, 0.81 mmol, 87%). ¹H NMR (CDCl₃, 300 MHz)67.43-7.46 (m, 3H), 7.74 (s, 1H), 7.85-7.88 (m, 2H); MS (DCl/NH₃) m/z242 (M+H⁺).

Example 262C5-(2-Phenyl-thiazol-5-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

The product of Example 262B (0.63 g, 2.6 mmol) was combined with theproduct of Example 6C (0.55 g, 2.6 mmol), Pd₂dba₃ (0.07 g, 0.08 mmol),BINAP (0.81 g, 1.3 mmol) and sodium tert-butoxide (0.50 g, 5.2 mmol) intoluene (15 mL) The mixture was stirred at 80° C. for 12 hours. Thereaction mixture was cooled to ambient temperature, diluted with ethylacetate, filtered through a pad of Celite and concentrated under reducedpressure. Purification by column chromatography (SiO₂, 0-10%methanol/methylene chloride gradient) afforded the title compound (0.73g, 1.96 mmol, 75% yield). ¹H NMR (CDCl₃, 300 MHz) δ1.46 (s, 9H),3.02-3.09 (m, 2H), 3.23 (m, 2H), 3.29-3.43 (s, 2H), 3.55 (dd, 2H, J=9.66Hz, 7.29 Hz), 3.63-3.70 (m, 2H), 6.73 (s, 1H), 7.30-7.41 (m, 3H), 7.79(d, 2H, J=7.1 Hz); MS (DCl/NH₃) m/z 372 (M+H⁺).

Example 262D 2-(2-Phenyl-thiazol-5-yl)-octahydro-pyrrolo[3,4-c]pyrroletrifluoroacetate

The product of Example 262C was processed according to methods FB and S2to provide the title compound: ¹H NMR (MeOH-d₄, 300 MHz) δ 3.19-3.29 (m,4H), 3.33-3.47 (m, 4H), 3.54-3.67 (m, 2H), 6.92 (s, 1H), 7.33-7.45 (m,3H), 7.74-7.77 (m, 2H); MS (DCl/NH₃) m/z 272 (M+H⁺). Anal. calculatedfor C₁₅H₁₇N₃S.C₂HF₃O₂: C, 52.98; H, 4.71; N, 10.90. Found: C, 52.71; H,4.63; N, 10.68.

Example 2632-Methyl-5-(2-phenyl-thiazol-5-yl)-octahydro-pyrrolo[3,4-c]pyrrolehydriodide

The product of Example 262C (0.12 g, 0.44 mmol) was converted to thefree amine by method FB. The amine was dissolved in methylene chloride(4 mL) and treated with methyl iodide (3.0 μL, 0.44 mmol). The reactionmixture was stirred at ambient temperature for 12 hours and thenconcentrated under reduced pressure. Purification by columnchromatography (SiO₂, 0-20% methanol/methylene chloride gradient)afforded 0.11 g (0.24 mmol, 54% yield). ¹H NMR (MeOH-d₄, 300 MHz) δ3.15-3.27 (m, 5H), 3.35-3.52 (m, 6H), 3.97 (m, 1H), 6.96 (m, 1H),7.34-7.45 (m, 3H), 7.74-7.78 (m, 2H); MS (DCl/NH₃) m/z 286 (M+H⁺). Anal.calculated for C₁₆H₁₉N₃S.HI: C, 46.49; H, 4.88; N, 10.17. Found: C,47.36; H, 5.17; N, 9.16.

Example 264 Example 264A5-(4-Bromo-thiazol-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

The product of Example 6C (0.1 g, 0.47 mmol) and 2,4-dibromothiazole(0.11 g, 0.94 mmol) was combined with N,N-diisopropylethylamine (0.02mL, 0.94 mmol) and the mixture was stirred at 110° C. for 1.5 hours. Thereaction mixture was cooled to ambient temperature, concentrated underreduced pressure, and purified by column chromatography (SiO₂, 20-40%ethyl acetate/hexanes gradient) to provide the title compound (0.13 g,0.34 mmol, 72% yield). ¹H NMR (CDCl₃, 300 MHz) δ 1.46 (s, 9H) 2.96-3.09(m, 2H) 3.18-3.47 (m, 4H) 3.58-3.77 (m, 4H) 6.37 (s, 1H); MS (DCl/NH₃)m/z 376 (M+H⁺).

Example 264B5-(4-Phenyl-thiazol-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

The product of Example 264A (0.11 g, 0.29 mmol) was combined withtributylphenyl tin (0.11 g, 0.29 mmol, Aldrich) and Pd(P^(t)Bu₃)₂ (0.020g, 0.030 mmol) in toluene (2 mL). The mixture was stirred at 100° C. for16 hours. Cesium fluoride (0.97 g, 0.64 mmol) was added to the reactionmixture after 20.5 hours. After an additional 5 hours time, the reactionmixture was cooled to ambient temperature, diluted with ethyl acetate,filtered through diatomaceous earth and purified by columnchromatography (SiO₂, 20-40% ethyl acetate/hexanes gradient) to providethe title compound (0.01 g, 0.026 mmol, 9% yield).

Example 264C 2-(4-Phenyl-thiazol-2-yl)-octahydro-pyrrolo[3,4-c]pyrroletosylate

The product of Example 264B was processed according to methods FB and S1to provide the title compound: ¹H NMR (MeOH-d₄, 300 MHz) δ 2.36 (s, 3H)3.20-3.28 (m, 3H) 3.55-3.73 (m, 6H) 6.98 (s, 1H) 7.19-7.40 (m, 5H) 7.70(d, J=8.5 Hz, 2H) 7.81 (d, J=8.5 Hz, 2H); MS (DCl/NH₃) m/z 272 (M+H⁺).Anal. calculated for C₁₅H₁₇N₃S.1.15C₇H₈O₃S: C, 58.98; H, 5.63; N, 8.95.Found: C, 58.67; H, 5.64; N, 8.96.

Examples 265-275 N-alkylation of2-(6-phenylpyridazin-3-yl)-octahydropyrrolo[3,4-c]pyrrole

The free base of the title compound (prepared as in Example 51) wasconverted to the indicated N-alkyl derivatives by reaction with thelisted N-alkylating agent according to the procedures described below.

Method K: The N-alkylating agent (0.39 mmol) and 1M Na₂CO₃ (aq, 0.5 mL)were added to a solution of2-(6-phenylpyridazin-3-yl)-octahydropyrrolo[3,4-c]pyrrole (98 mg, 0.37mmol) in THF (0.5 mL). The mixture was stirred for 2 h, then dilutedwith dichloromethane (5 mL) and washed with water (2 mL). The organicphase was concentrated and the residue was purified by columnchromatography to provide the N-alkylated product, which was convertedto a salt by the listed procedure.Method L: A solution of the N-alkylating agent (a carboxylic acid, 0.41mmol) and carbonyldiimidazole (63 mg, 0.39 mmol) in DMF (0.4 mL) wasstirred for 1 h, then treated with a solution of2-(6-phenylpyridazin-3-yl)-octahydropyrrolo[3,4-c]pyrrole (89 mg, 0.33mmol) in DMF (1 mL). The mixture was heated to 50° C. for 12 h, thendiluted with CH₂Cl₂, washed with 0.2 M NaOH, dried over K₂CO₃ andconcentrated. The residue was purified by column chromatography toprovide the N-acyl intermediate. This was taken in THF (2 mL) and addeddropwise to an ice-cooled mixture of LiAlH₄ (26 mg, 0.68 mmol) in THF 1mL). The mixture was warmed to room temperature, heated to 50° C. for 15min, then stirred at room temperature for 1 h. The reaction was quenchedwith excess Na₂SO₄.10H₂O, and filtered with an ethyl acetate rinse. Thefiltrate was concentrated and the residue purified by columnchromatography to provide the N-alkyl derivative, which was converted toa salt by the listed method.Method M: To a solution of2-(6-phenylpyridazin-3-yl)-octahydropyrrolo[3,4-c]pyrrole (0.11 g, 0.41mmol) in the N-alkylating agent (a ketone or aldehyde, 7 mL) was addedNaBH(OAc)₃ (0.11 g, 0.53 mmol). The mixture was stirred at roomtemperature for 18 h, then concentrated under reduced pressure. Thecrude material was partitioned with CH₂Cl₂ (5 mL) and saturated, aqueousNaHCO₃ (3 mL), and the aqueous layer was further extracted with CH₂Cl₂(3×5 mL). The combined extract was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified via column chromatography to provide the alkylated amine,which was converted to a salt by the listed procedure.

N-alkylating Example Agent Conditions Resulting Compound 265 Benzylbromide 1) K 2-Benzyl-5-(6-phenylpyridazin-3-yl)-octahydropyrrolo[3,4-2) S3 c]pyrrole hydrochloride ¹H NMR (MeOH-d₄, 300 MHz) δ 3.11-3.32 (m,4H), 3.56-3.87 (m, 6H), 4.36 (s, 2H), 7.17 (d, J = 9 Hz, 1H), 7.38-7.58(m, 8H), 7.86-7.99 (m, 3H); MS (DCI/NH₃) m/z 357 (M + H)⁺; Anal.C₂₃H₂₄N₄•1.05HCl: C, H, N. 266 4-chloromethyl 1) K2-(6-Phenylpyridazin-3-yl)-5-(pyridin-4-ylmethyl)- pyridine 2) S4octahydropyrrolo[3,4-c]pyrrole bis(trifluoroacetate) ¹H NMR (MeOH-d₄,300 MHz) δ 3.13-3.52 (m, 6H), 3.73-3.91 (m, 4H), 4.30 (s, 2H), 7.46-7.59(m, 4H), 7.66 (d, J = 6 Hz, 2H), 7.92-8.02 (m, 2H), 8.18 (d, J = 10 Hz,1H), 8.67 (d, J = 5 Hz, 2H); MS (DCI/NH₃) m/z 358 (M + H)⁺; Anal.C₂₂H₂₃N₅•2C₂HF₃O₂: C, H, N. 267 2-chloromethyl 1) K2-(6-Phenylpyridazin-3-yl)-5-(pyridin-2-ylmethyl)- pyridine 2) S4octahydropyrrolo[3,4-c]pyrrole bis(trifluoroacetate) ¹H NMR (MeOH-d₄,300 MHz) δ 3.36-3.51 (m, 4H), 3.75-3.96 (m, 6H), 4.61 (s, 2H), 7.41-7.58(m, 6H), 7.90 (td, J = 8, 2 Hz, 1H), 7.93-7.99 (m, 2H), 8.15 (d, J = 10Hz, 1H), 8.67 (d, J = 4 Hz, 1H); MS (DCI/NH₃) m/z 358 (M + H)⁺; Anal.C₂₂H₂₃N₅•2C₂HF₃O₂: C, H, N. 268 2-chloro-5- 1) K2-(6-Chloropyridin-3-ylmethyl)-5-(6-phenylpyridazin-3-yl)- chloromethyl2) S3 octahydropyrrolo[3,4-c]pyrrole hydrochloride pyridine ¹H NMR(MeOH-d₄, 300 MHz) δ 3.04-3.22 (m, 2H), 3.23-3.61 (m, 4H), 3.65-3.83 (m,4H), 4.26 (s, 2H), 7.26 (d, J = 9 Hz, 1H), 7.41-7.59 (m, 4H), 7.89-8.03(m, 4H), 8.47 (d, J = 2 Hz, 1H); MS (DCI/NH₃) m/z 392, 394 (M + H)⁺;Anal. C₂₂H₂₂ClN₅•HCl: C, H, N. 269 3-Pyridylacetic 1) L2-(6-Phenylpyridazin-3-yl)-5-(2-pyridin-3-ylethyl)- acid 2) S4octahydropyrrolo[3,4-c]pyrrole bis(trifluoroacetate) ¹H NMR (CD₃OD, 300MHz) δ 3.17 (m, 2H), 3.38-3.61 (m, 4H), 3.76-3.95 (m, J = 2 Hz, 4H),7.47-7.61 (m, 5H), 7.93-8.02 (m, 3H), 8.20 (d, J = 10 Hz, 1H), 8.54 (dd,J = 5, 1 Hz, 1H), 8.58 (d, J = 1 Hz, 1H); MS (DCI/NH₃) m/z 372 (M + H)⁺;Anal. C₂₃H₂₅N₅•2.05C₂HF₃O₄: C, H, N. 270 3-bromomethyl 1) K2-(6-Phenylpyridazin-3-yl)-5-(pyridin-3-ylmethyl)- pyridine 2) S4octahydropyrrolo[3,4-c]pyrrole bis(trifluoroacetate) hydrobromide ¹H NMR(MeOH-d₄, 300 MHz) δ 3.40-3.54 (m, 4H), 3.63-3.76 (m, 2H), 3.82-3.95 (m,4H), 4.49 (s, 2H), 7.54-7.58 (m, 3H), 7.60 (ddd, J = 8, 5, 1 Hz, 1H),7.66 (d, J = 10 Hz, 1H), 7.93-8.01 (m, 2H), 8.09 (ddd, J = 8, 2 Hz, 1H),8.32 (d, J = 10 Hz, 1H), 8.68 (dd, J = 5, 1 Hz, 1H), 8.73 (d, J = 2 Hz,1H); MS (DCI/NH₃) m/z 358 (M + H)⁺; Anal. C₂₂H₂₃N₅•2.5C₂HF₃O₂: C, H, N.271 Allyl iodide 1) K2-Allyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4- 2) S1c]pyrrole bis-p-toluenesulfonate) ¹H NMR (300 MHz, CD₃OD) δ ppm 2.28 (s,6H), 3.24 (m, 1H), 3.50 (m, 3H), 3.89 (m, 8H), 5.58 (m, 2H), 6.03 (m,1H), 7.17 (d, J = 8.1 Hz, 4H), 7.58 (m, 3H), 7.64 (d, J = 8.1 Hz, 4H),7.73 (dd, J = 27.5, 9.5 Hz, 1H), 7.96 (m, 2H), 8.30 (dd, J = 23.9, 9.7Hz, 1H); MS (DCI/NH₃) m/z 307 (M + H)⁺; Anal. calculated forC₁₉H₂₂N₄•2C₇H₈O₃S•0.5H₂O: C, 60.07; H, 5.96; N, 8.49. Found: C, 60.37;H, 5.68; N, 8.52. 272 Crotonaldehyde 1) M2-But-2-enyl-5-(6-phenyl-pyridazin-3-yl)-octahydro- 2) S1pyrrolo[3,4-c]pyrrole bis-p-toluenesulfonate ¹H NMR (300 MHz, CD₃OD) δppm 1.78 (d, J = 5.8 Hz, 3H), 2.31 (s, 6H), 3.14 (m, 2H), 3.48 (m, 2H),3.87 (m, 8H), 5.83 (m, 2H), 7.18 (d, J = 7.8 Hz, 4H), 7.58 (m, 3H), 7.66(m, 4H), 7.73 (dd, J = 25.1, 10.2 Hz, 1H), 7.97 (m, 2H), 8.31 (dd, J =22.4, 9.8 Hz, 1H); MS (DCI/NH₃) m/z 321 (M + H)⁺; Anal. calculated forC₂₀H₂₄N₄•2C₇H₈O₃S: C, 61.42; H, 6.06; N, 8.43. Found: C, 61.15; H, 5.83;N, 8.40. 273 Acetaldehyde 1) M2-Ethyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4- 2) S1c]pyrrole bis-p-toluenesulfonate ¹H NMR (300 MHz, CD₃OD) δ ppm 1.37 (q,J = 7.7 Hz, 3H), 2.30 (s, 6H), 3.41 (m, 6H), 3.94 (m, 6H), 7.18 (d, J =7.8 Hz, 4H), 7.58 (m, 3H), 7.65 (d, J = 8.1 Hz, 4H), 7.74 (dd, J = 28.1,10.2 Hz, 1H), 7.96 (d, J = 3.7 Hz, 2H), 8.32 (dd, J = 27.0, 10.0 Hz,1H); MS (DCI/NH₃) m/z 295 (M + H)⁺; Anal. calculated forC₁₈H₂₂N₄•2C₇H₈O₃S: C, 60.17; H, 6.00; N, 8.77. Found: C, 59.74; H, 5.98;N, 8.68. 274 Propionaldehyde 1) M2-(6-Phenyl-pyridazin-3-yl)-5-propyl-octahydro-pyrrolo[3,4- 2) S1c]pyrrole tris-p-toluenesulfonate) ¹H NMR (300 MHz, CD₃OD) δ ppm 1.01(q, J = 7.5 Hz, 3H), 1.76 (m, 1H), 2.31 (s, 9H), 3.33 (m, 6H), 3.94 (m,7H), 7.19 (d, J = 8.1 Hz, 6H), 7.58 (m, 3H), 7.66 (m, 6H), 7.75 (m, J =30.8 Hz, 1H), 7.97 (m, 2H), 8.31 (dd, J = 28.6, 9.7 Hz, 1H); MS(DCI/NH₃) m/z 309 (M + H)⁺; Anal. calculated forC₁₉H₂₄N₄•3C₇H₈O₃S•0.8NH₃: C, 57.29; H, 6.06; N, 8.02. Found: C, 57.67;H, 5.58; N, 8.41. 275 Acetone 1) M2-Isopropyl-5-(6-phenyl-pyridazin-3-yl)-octahydro- 2) S1pyrrolo[3,4-c]pyrrole bis-p-toluenesulfonate ¹H NMR (300 MHz, CD₃OD) δppm 1.40 (d, J = 6.8 Hz, 3H), 1.44 (d, J = 6.8 Hz, 3H), 2.30 (s, 6H),3.24 (m, 1H), 3.51 (m, 4H), 3.94 (m, 6H), 7.18 (d, J = 8.1 Hz, 4H), 7.58(m, 3H), 7.65 (d, J = 8.1 Hz, 4H), 7.70 (m, 1H), 7.97 (m, 2H), 8.30 (dd,J = 31.9, 9.8 Hz, 1H); MS (DCI/NH₃) m/z 309 (M + H)⁺; Anal. calculatedfor C₁₉H₂₄N₄•2C₇H₈O₃S: C, 60.71; H, 6.18; N, 8.58. Found: C, 60.45; H,5.99; N, 8.47.

Examples 276-281

5-aryl-2-benzenesulfanyl-1,3,4-oxadiazole derivatives were prepared fromthe commercially available 5-aryl-1,3,4-oxadiazolyl-2-thiols accordingto the following procedure:

Example 276A 2-Benzylsulfanyl-5-phenyl-[1,3,4]oxadiazole

5-Phenyl-[1,3,4]oxadiazole-2-thiol (Aldrich, 3.1 g, 17.4 mmol) was addedto EtOH (30 mL) and cooled to 0° C. while stirring.Diisopropylethylamine (3.1 mL, 17.4 mmol) was then added and the mixturebecame a clear solution. Benzyl bromide (2.08 mL, 17.4 mmol) was addedand the resulting mixture was allowed to warm to room temperature whilestirring. After 45 min, a thick white precipitate formed. The mixturewas stirred an additional 1 hr followed by the addition of 1M NaOH (3mL). The mixture was filtered, washed with 1M NaOH (2×20 mL), 3% citricacid (2×20 mL), H₂O (2×20 mL) and the precipitate was dried under vacuumto afford 4.31 g (92%) 2-benzylsulfanyl-5-phenyl-[1,3,4]oxadiazole as awhite solid. ¹H NMR (CDCl₃, 300 MHz) δ 4.57 (s, 2H), 7.37 (m, 3H), 7.48(m, 5H), 7.99 (m, 2H); MS (DCl/NH₃) m/z 269 (M+H)⁺.

Example 276B(3aR,6aR)-5-(5-Phenyl-[1,3,4]oxadiazol-2-yl)-hexahydro-pyrrolo[3,4-b]pyrrole-1-carboxylicacid tert-butyl ester

To provide the title compound, the product of Example 14H, 0.20 g, 0.95mmol) and diisopropylethylamine (0.17 mL, 0.95 mmol) were dissolved in1,2-dichlorobenzene (3 mL). The2-benzylsulfanyl-5-aryl-[1,3,4]oxadiazole (0.23 g, 0.86 mmol, preparedaccording to the procedure of Example 276A) was added and the mixtureheated to 220° C. under microwave irradiation for 15 min. After cooling,the reaction mixture was diluted with CH₂Cl₂ (25 mL), washedsuccessively with sat. NaHCO₃ (10 mL), H₂O (10 mL), and brine (10 mL),dried (Na₂SO₄) and concentrated under vacuum. The residue was purifiedby column chromatography (100% CH₂Cl₂ to 95/5/0.5 CH₂Cl₂:MeOH:NH₄OH) toprovide the title compound (56 mg, 18%) as a yellow solid: ¹H NMR(CD₃OD, 300 MHz) δ 1.48 (s, 9H), 1.78-1.93 (m, 1H), 2.04-2.21 (m, 1H),3.16 (m, 1H), 3.42-3.57 (m, 3H), 3.68-3.90 (m, 3H), 4.42 (m, 1H), 7.51(m, 3H), 7.89 (m, 2H); MS (DCl/NH₃) m/z 357 (M+H)⁺. The product wascarried through deprotection and/or salt formation steps as listed inthe table below.

Examples 276-281

General Coupling Procedure (OD): The diamine (1 mmol) anddiisopropylethylamine (1-2 mmol) were dissolved in 1,2-dichlorobenzene(3 mL). A 5-aryl-substituted 2-benzylsulfanyl-[1,3,4]oxadiazole (1-2mmol) was added and the mixture heated to 220° C. under microwaveirradiation for 15 min. After cooling, the reaction mixture was dilutedwith CH₂Cl₂ (25 mL), washed successively with sat. NaHCO₃ (10 mL), H₂O(10 mL), and brine (10 mL), dried (Na₂SO₄) and concentrated undervacuum. The residue was purified by column chromatography. Examples276-281 were prepared by reacting the 2-benzylsulfanyl-[1,3,4]oxadiazolederivative substituted at the 5-position with the listed aryl group andthe corresponding diamine according to the conditions listed in thetable below.

Example Aryl Diamine Conditions Resulting Compound 276 Phenyl Example14H 1) OD (3aR,6aR)-5-(5-Phenyl-[1,3,4]oxadiazol-2-yl)- 2) FBoctahydro-pyrrolo[3,4-b]pyrrole ¹H NMR (CD₃OD, 300 MHz) δ 1.72-1.83 (m,1H), 2.02-2.18 (m, 1H), 2.88-3.06 (m, 3H), 3.40-3.46 (m, 1H), 3.57-3.63(m, 1H), 3.71-3.81 (m, 2H), 3.94-4.00 (m, 1H), 7.52 (m, 3H), 7.90 (m,2H); MS (DCI/NH₃) m/z 257 (M + H)⁺; Anal. C₁₄H₁₆N₄O•0.67H₂O: C, H, N 277Phenyl Example 6C 1) B 2-(5-Phenyl-[1,3,4]oxadiazol-2-yl)-octahydro- 2)FB pyrrolo[3,4-c]pyrrole bis hydrochloride 3) S3 ¹H NMR (DMSO-d₆, 300MHz) δ 3.06-3.25 (m, 4H) 3.38-3.47 (m, 2H) 3.52-3.63 (m, 2H) 3.65-3.76(m, 2H) 7.51-7.58 (m, 3H) 7.82-7.90 (m, 2H) 9.17 (s, 2H); MS (DCI/NH₃)m/z 257 (M + H)⁺; Anal. C₁₄H₁₆N₄O•1.8HCl: C, H, N. 278 p-methoxy Example6C 1) B 2-[5-(4-Methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]- phenyl 2) FBoctahydro-pyrrolo[3,4-c]pyrrole trifluoroacetate 3) S4 ¹H NMR (DMSO-d₆,300 MHz) δ 3.08-3.21 (m, 4H) 3.37-3.49 (m, 2H) 3.49-3.57 (m, 2H)3.61-3.71 (m, 2H) 3.83 (s, 3H) 7.06-7.14 (m, 2H) 7.75-7.83 (m, 2H) 8.88(s, 2H); MS (DCI/NH₃) m/z 287 (M + H)⁺; Anal. C₁₅H₁₈N₄O₂•C₂HF₃O₂: C, H,N. 279 p-methoxy Example 6C 1) B2-[5-(4-Methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]- pheny 2) FB5-methyl-octahydro-pyrrolo[3,4-c]pyrrole 3) RA hydrochloride 4) S3 ¹HNMR (DMSO-d₆, 300 MHz) δ 2.81 (dd, J = 6.6, 4.9 Hz, 3H) 2.86-2.96 (m,1H) 3.04-3.20 (m, 1H) 3.23-3.36 (m, 2H) 3.47-3.58 (m, 2H) 3.59-3.66 (m,2H) 3.66-3.82 (m, 2H) 3.83 (s, 3H) 7.05-7.16 (m, 2H) 7.75-7.86 (m, 2H);MS (DCI/NH₃) m/z 301 (M + H)⁺; Anal. C₁₆H₂₀N₄O₂•1.3HCl: C, H, N. 280p-chloro Example 6C 1) B 2-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-phenyl 2) FB octahydro-pyrrolo[3,4-c]pyrrole trifluoroacetate 3) S4 ¹HNMR (DMSO-d₆, 300 MHz) δ 3.11-3.22 (m, 4H) 3.38-3.49 (m, 2H) 3.51-3.59(m, 2H) 3.64-3.74 (m, 2H) 7.44-7.75 (m, 2H) 7.79-8.00 (m, 2H) 8.97 (s,2H); MS (DCI/NH₃) m/z 291 (M + H)⁺; Anal. C14H15ClN4O•3.7C2HF3O2: C, H,N. 281 Phenyl Example 5D 1) B6-Methyl-3-(5-phenyl-[1,3,4]oxadiazol-2-yl)-3,6- 2) S4diaza-bicyclo[3.2.1]octane bis trifluoroacetate ¹H NMR (MeOD-d₄, 300MHz) δ 2.07-2.28 (m, 1H) 2.41-2.56 (m, 1H) 2.88-2.97 (m, 1H) 2.99 (s,3H) 3.24 (dd, J = 12.4, 5.6 Hz, 1H) 3.35-3.59 (m, 2H) 3.74-4.00 (m, 2H)4.01-4.31 (m, 2H) 7.40-7.68 (m, 3H) 7.84-8.07 (m, 2H); MS (DCI/NH₃) m/z271 (M + H)⁺; Anal. C15H18N4O•2.2C2HF3O2: C, H, N.

Example 282 2-(2-Methoxy-biphenyl-4-yl)-octahydro-pyrrolo[3,4-c]pyrroleExample 282A5-(3-Methoxy-phenyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acidtert-butyl ester

The product of Example 6C (1.0 g, 4.71 mmol), 3-bromoanisole (1.15 g,6.12 mmol), tris(dibenzylideneacetone)dipalladium (0) (Pd₂(dba)₃, Strem,86 mg, 0.094 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(BINAP, Strem, 0.117 g, 0.188 mmol), and tert-BuONa (0.724 g, 7.54 mmol)were combined in 20 mL toluene. This mixture was warmed to 85° C. andstirred for 18 h then was cooled to ambient temperature, filtered andconcentrated under reduced pressure. The crude residue was purified viaflash column chromatography (SiO₂, 50% hexanes-EtOAc) to give 1.45 g ofthe title compound (4.6 mmol, 97% yield). MS (DCl/NH₃) m/z 319 (M+H)⁺.

Example 282B5-(4-Iodo-3-methoxy-phenyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

To the product of Example 282A (0.7 g, 2.2 mmol) in 30 mL CH₂Cl₂ atambient temperature was added 1.16 g of TIOAc (Aldrich, 4.4 mmol) asdescribed in Pirrung, M., et al, JACS, 2001, 123, 3638-3643. Thismixture was stirred for 5 min then I₂ (0.67 g, 2.64 mmol) in CH₂Cl₂ (70mL) was added dropwise. Thallium (I) iodide formed a precipitate in thecourse of this reaction. This mixture stirred at ambient temperature for2 h then was filtered. The filtrate was washed with 10% aqueous Na₂S₂O₃(15 mL), NaHCO₃ (10 mL), and saturated, aqueous NaCl (10 mL). Theorganic material was concentrated under reduced pressure and purifiedvia flash column chromatography (SiO₂, 50% hexanes-EtOAc) to provide thetitle compound (0.68 g, 70% yield). MS (DCl/NH₃) m/z 445 (M+H)⁺.

Example 282C5-(2-Methoxy-biphenyl-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

The product of Example 282B (0.68 g, 1.53 mmol), phenylboronic acid(Aldrich, 0.59 g, 3.07 mmol), tris(dibenzylideneacetone)dipalladium (0)(Pd₂(dba)₃, Strem, 56 mg, 0.061 mmol),1,3-bis(2,6-di-1-propylphenyl)imidazolium chloride (Strem, 65 mg, 0.15mmol), and 2M Na₂CO₃ (aq, 4 mL) were combined in toluene (20 mL). Themixture was warmed to 85° C. and stirred for 18 h; however, the mixturecontained mostly starting material, so additional Pd₂(dba)₃ (56 mg,0.061 mmol) and 1,3-bis(2,6-di-1-propylphenyl)imidazolium chloride (65mg, 0.15 mmol) were added and the mixture stirred for another 18 h at85° C. The reaction was cooled to ambient temperature, filtered,concentrated under reduced pressure and purified by columnchromatography (SiO₂, 50% hexanes-EtOAc) to give the title compound(0.17 g, 28% yield). MS (DCl/NH₃) m/z 395 (M+H)⁺.

Example 282D 2-(2-Methoxy-biphenyl-4-yl)-octahydro-pyrrolo[3,4-c]pyrroletrifluoroacetate

To the product of Example 282C (0.17 g, 0.43 mmol) in 6 mL CH₂Cl₂ wasadded 3 mL trifluoroacetic acid (TFA) according to the general procedureto give 0.122 g of the title compound (0.30 mmol, 69% yield). ¹H NMR(CH₃OH-d₄, 300 MHz) δ 3.25 (m, 4H), 3.35 (m, 2H), 3.52 (m, 2H), 3.62 (m,2H), 3.78 (s, 3H), 6.41 (dd, J=6.8, 2.4 Hz, 1H), 6.42 (s, 1H), 7.18 (m,2H), 7.31 (m, 2H), 7.42 (m, 2H); MS (DCl/NH₃) m/z 295 (M+H)⁺; Anal.calculated for C₁₉H₂₂N₂O.CF₃CO₂H: C, 61.76; H, 5.68; N, 6.86. Found: C,62.03; H, 5.91; N, 7.02.

Example 2832-(2-Methoxy-biphenyl-4-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrroleExample 283A2-(2-Methoxy-biphenyl-4-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole

To the product of Example 282D (0.102 g, 0.25 mmol) in 3 mL 37% aqueousHCHO was added 54 mg NaBH(OAc)₃ (0.25 mmol). This material stirred atambient temperature for 4 h then was quenched with 5 mL saturated,aqueous NaHCO₃. CH₂Cl₂ (5 mL) was added, the layers separated and theaqueous layer was extracted 3×5 mL CH₂Cl₂. The combined organics weredried over Na₂SO₄, concentrated under reduced pressure and purified viaflash column chromatography (SiO₂, 1% NH₄OH:9% CH₃OH:90% CH₂Cl₂) to give69 mg of the title compound (2.24 mmol, 90% yield) which was carried onto the next reaction without further purification.

Example 283B2-(2-Methoxy-biphenyl-4-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrolep-toluenesulfonate

To the product of Example 283A (69 mg, 0.224 mmol) in 3 mL 10% EtOH inEtOAc was added p-toluenesulfonic acid (p-TsOH.H₂O, 45 mg, 0.24 mmol) in2 mL 10% EtOH in EtOAc. Diethyl ether (1 mL) was added and the mixturestirred at ambient temperature until a precipitate formed. Filtrationyielded 28 mg of the title compound (0.043 mmol, 19% yield). ¹H NMR(CH₃OH-d₄, 300 MHz) δ 2.35 (s, 6H), 2.92 and 2.98 (rotamer s, 3H), 3.19(m, 3H) 3.38 (m, 3H), 3.63 (m, 3H), 3.77 (s, 3H), 3.98 (m, 1H), 6.50 (m,1H), 6.52 (s, 1H), 7.16 (m, 1H), 7.22 (m, 5H), 7.32 (m, 2H), 7.42 (m,2H), 7.70 (m, 4H); MS (DCl/NH₃) m/z 309 (M+H)⁺; Anal. calculated forC₂₀H₂₄N₂O.2C₇H₈O₃S: C, 62.55; H, 6.18; N, 4.29. Found: C, 62.17; H,5.95; N, 4.18.

Example 284 4-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-biphenyl-2-oldi-bromide

Demethylation Procedure (deMe): A solution of the product of Example282C (0.28 g, 0.71 mmol) in CH₂Cl₂ (15 mL) was cooled to −78° C. andBBr₃ (2.8 mL of a 1 M solution in heptane, 2.8 mmol) was added dropwisevia syringe. The mixture was stirred at −78° C. for 30 min then wasallowed to warm to room temperature and stirred for an additional 3 h.The mixture was cooled to −78° C. and ˜3 mL CH₃OH was added dropwise andthe mixture was allowed to warm to ambient temperature. Afterconcentration under reduced pressure, 5 mL of 10% CH₃OH in EtOAc wasadded. The resulting solids were isolated via filtration to give 0.25 gof the title compound (0.56 mmol, 80% yield). ¹H NMR (300 MHz, CD₃OD) δppm 3.32 (m, 6H), 3.50 (dd, J=9.8, 1.7 Hz, 2H), 3.61 (m, 2H), 7.16 (t,J=4.4 Hz, 1H), 7.21 (m, 1H), 7.33 (m, 3H), 7.50 (m, 3H); MS (DCl/NH₃)m/z 281 (M+H)⁺; Anal. calculated for C₁₈H₂₀N₂O.2HBr: C, 48.89; H, 5.01;N, 6.34. Found: C, 48.53; H, 5.04; N, 6.14.

Example 2854-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-biphenyl-2-olbis-p-toluenesulfonate

The product of Example 284 was processed according to the methods RA andS1 to provide the title compound 7% yield). ¹H NMR (300 MHz, CD₃OD) δ2.36 (s, 6H), 2.91 (s, 3H), 3.18 (m, 6H), 3.52 (m, 4H), 7.13 (m, 1H),7.22 (m, 5H), 7.40 (m, 5H), 7.69 ppm (m, 5H); MS (DCl/NH₃) m/z 295(M+H)⁺; Anal. calculated for C₁₉H₂₂N₂O.1.7C₇H₈O₃S: C, 63.21; H, 6.11; N,4.77. Found: C, 62.93; H, 5.68; N, 5.10.

Example 286 Example 286A5-[6-(3-Methoxy-phenyl)-pyridazin-3-yl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

The product of Example 90 (0.50 g, 1.5 mmol), m-methoxy-phenylboronicacid (0.47 g, 3.1 mmol), aqueous Na₂CO₃ (2M, 2.5 mL),tris(dibenzylideneacetone)dipalladium (0) (Pd₂(dba)₃, Strem, 56 mg,0.062 mmol) and 1,3-bis(2,6-di-1-propylphenyl)imidazolium chloride(Strem, 65 mg, 0.15 mmol) were combined in toluene (20 mL) were combinedin toluene (20 mL). The mixture was deoxygenated by three vacuum/N₂purge cycles. The mixture was stirred under nitrogen at 85° C. for 18 hthen cooled to room temperature, filtered, concentrated under reducedpressure and purified by column chromatography (SiO₂, 50% hexanes inethyl acetate) to provide the title compound (0.51 g, 84% yield). MS(DCl/NH₃) m/z 397 (M+H)⁺.

Example 286B3-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenoldihydrobromide

The product of Example 286A (0.63 g, 1.6 mmol) was processed accordingto the procedure ‘deMe’ as described in Example 284 to provide the titlecompound (0.77 g) as a crude solid, suitable for the next reaction: MS(DCl/NH₃) m/z 283 (M+H)⁺.

Example 286C5-[6-(3-Hydroxy-phenyl)-pyridazin-3-yl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

The product of Example 286B (˜1.6 mmol) was dissolved in THF (15 mL).Aqueous NaHCO₃ (2M, 4 mL) was added, followed by di-tert-butyldicarbonate (0.49 g, 2.2 mmol). This mixture was stirred at ambienttemperature for 1 h then extracted CH₂Cl₂ (2×5 mL). The combined extractwas washed with brine (3 mL), dried over anhydrous Na₂SO₄, concentratedunder reduced pressure and purified by column chromatography (SiO₂, 1%NH₄OH:9% CH₃OH:90% CH₂Cl₂) to provide the title compound (0.34 g, 56%from Example 286A). MS (DCl/NH₃) m/z 383 (M+H)⁺.

Example 286D3-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenoltri-hydrochloride

The product of Example 286C was processed according to the methods FBand S3 to provide the title compound in 29% yield: ¹H NMR (300 MHz,CD₃OD) δ ppm 3.31 (m, 4H), 3.70 (m, 6H), 6.86 (ddd, J=8.0, 2.4, 1.2 Hz,1H), 7.12 (d, J=9.5 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.37 (m, 2H), 7.85(d, J=9.5 Hz, 1H); MS (DCl/NH₃) m/z 283 (M+H)⁺; Anal. calculated forC₁₆H₁₈N₄O.3.8HCl.1.3NH₄OH: C, 41.20; H, 6.12; N, 15.91. Found: C, 40.90;H, 6.27; N, 16.26.

Example 2874-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenolbis-trifluoroacetate Example 287A4-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenoldihydrobromide

The product of Example 95 was processed according to the procedure deMEas described in Example 284 to provide the title compound as a crudesalt in 89% yield: MS (DCl/NH₃) m/z 283 (M+H)⁺.

Example 287B5-[6-(4-Hydroxy-phenyl)-pyridazin-3-yl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

The product of Example 287A was treated with di-tert-butyl dicarbonateaccording to the procedure Boc as described in Example 286C to providethe crude title compound: MS (DCl/NH₃) m/z 383 (M+H)⁺.

Example 287C4-[6-(Hexahydro-pyrrolo[3,4-c]Pyrrol-2-yl)-pyridazin-3-yl]-phenolbis-trifluoroacetate

The product of Example 287B was processed according to the methods FBand S4 to provide the title compound in 87% yield: ¹H NMR (300 MHz,CD₃OD) δ ppm 3.37 (m, 4H), 3.66 (dd, J=11.5, 7.1 Hz, 2H), 3.74 (dd,J=11.7, 3.2 Hz, 2H), 3.93 (m, 2H), 6.96 (m, 2H), 7.65 (d, J=9.8 Hz, 1H),7.83 (m, 2H), 8.29 (d, J=9.8 Hz, 1H); MS (DCl/NH₃) m/z 282 (M+H)⁺; Anal.calculated for C₁₆H₁₈N₄O.2.4CF₃CO₂H: C, 44.93; H, 3.70; N, 10.08. Found:C, 45.16; H, 3.61; N, 10.22.

Example 288Diethyl-(2-{3-[6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenoxy}-ethyl)-aminebis-p-toluenesulfonate Example 288A5-{6-[3-(2-Diethylamino-ethoxy)-phenyl]-pyridazin-3-yl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

Polymer-bound triphenylphosphine (Aldrich, 0.61 g, 1.8 mmol) was addedto an ice-cooled solution of the product of Example 286C (0.28 g, 0.73mmol) and N,N-diethylethanolamine (0.24 mL, 1.8 mmol) in CH₂Cl₂.Di-iso-propyl-azodicarboxylate (Aldrich, 0.36 mL, 1.8 mmol) was addeddropwise via syringe. This mixture was stirred at 0° C. for 1 h thenkept at room temperature for 72 h. The reaction mixture was filteredthrough diatomaceous earth, concentrated under reduced pressure andpurified by column chromatography (SiO₂, 1% NH₄OH:9% CH₃OH:90% CH₂Cl₂)to provide the title compound (0.19 g, 54% yield). MS (DCl/NH₃) m/z 482(M+H)⁺.

Example 288BDiethyl-(2-{3-[6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenoxy}-ethyl)-aminebis-p-toluenesulfonate

The product of Example 288A (0.18 g, 0.37 mmol) was processed accordingto the methods FB and S1 to provide the title compound in 43% yield: ¹HNMR (300 MHz, CD₃OD) δ ppm 1.39 (t, J=7.3 Hz, 6H), 1.38 (s, 6H), 3.32(m, 8H), 3.71 (m, 8H), 4.44 (dd, J=4.8 Hz, 2H), 7.11 (dd, J=7.6, 2.2 Hz,1H), 7.21 (m, 5H), 7.46 (t, J=8.0 Hz, 1H), 7.57 (m, 1H), 7.67 (m, 5H),7.97 (d, J=9.5 Hz, 1H); MS (DCl/NH₃) m/z 382 (M+H)⁺; Anal. calculatedfor C₂₂H₃₁N₅O.2C₇H₈O₃S.1.1H₂O: C, 57.98; H, 6.65; N, 9.39. Found: C,57.67; H, 6.64; N, 9.11.

Example 289Diethyl-(2-{4-[6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenoxy}-ethyl)-aminetris-trifluoroacetate

The product of Example 287B was processed successively according to theprocedures of Example 288A, FB, and S4 to provide the title compound: ¹HNMR (300 MHz, CD₃OD) δ ppm 1.39 (t, J=7.3 Hz, 6H), 3.37 (m, 8H), 3.65(m, 4H), 3.76 (dd, J=11.2, 2.7 Hz, 2H), 3.91 (m, 2H), 4.45 (m, 2H), 7.19(m, 2H), 7.53 (d, J=9.8 Hz, 1H), 7.98 (m, 2H), 8.21 (d, J=9.8 Hz, 1H);MS (DCl/NH₃) m/z 382 (M+H)⁺; Anal. calculated for C₂₂H₃₁N₅O.3CF₃CO₂H: C,46.48; H, 4.74; N, 9.68. Found: C, 46.56; H, 4.72; N, 9.55.

Example 290(2-{4-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-phenoxy}-ethyl)-dimethyl-aminetris-trifluoroacetate

The product of Example 287B was coupled to N,N-dimethylethanolamineaccording to the procedure of Example 288A. The product was furtherprocessed according to the methods FB and S4 to provide the titlecompound: ¹H NMR (300 MHz, CD₃OD) δ ppm 3.01 (s, 6H), 3.39 (m, 4H), 3.65(m, 4H), 3.76 (m, 2H), 3.91 (m, 2H), 4.44 (m, 2H), 7.19 (m, 2H), 7.53(d, J=9.5 Hz, 1H), 7.98 (m, 2H), 8.20 (d, J=9.8 Hz, 1H); MS (DCl/NH₃)m/z 354 (M+H)⁺; Anal. calculated for C₂₀H₂₇N₅O.3CF₃CO₂H: C, 44.90; H,4.35; N, 10.07. Found: C, 44.85; H, 4.16; N, 9.92.

Examples 291-294

The N-methyl derivatives of Examples 286-290 were prepared according tothe methods indicated in the table below:

Example Starting Material Conditions Resulting Compound 291 Example286 1) RA 3-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol- 2) S32-yl)-pyridazin-3-yl]-phenol tri-hydrochloride ¹H NMR (300 MHz, CD₃OD) δppm 2.96 (s, 3H), 3.31 (m, 4H), 3.61 (m, 6H), 6.86 (ddd, J = 7.9, 2.5,1.2 Hz, 1H), 7.16 (d, J = 9.5 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.37(m, 2H), 7.86 (d, J = 9.5 Hz, 1H); MS (DCI/NH₃) m/z 297 (M + H)⁺; Anal.calculated for C₁₇H₂₀N₄O•2.5HCl•0.75H₂O: C, 50.91; H, 6.03; N, 13.97.Found: C, 51.03; H, 6.36; N, 13.98. 292 Example 287 1) RA4-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol- 2) S12-yl)-pyridazin-3-yl]-phenol bis-p- toluenesulfonate ¹H NMR (300 MHz,CD₃OD) δ ppm 2.31 (m, 6H), 3.00 (s, 3H), 3.20 (m, 1H), 3.47 (m, 3H),3.89 (m, 6H), 6.97 (m, 2H), 7.19 (m, 4H), 7.65 (m, 5H), 7.81 (d, J = 8.5Hz, 2H), 8.24 (dd, J = 24.8, 10.9 Hz, 1H); MS (DCI/NH₃) m/z 297 (M +H)⁺; Anal. calculated for C₁₇H₂₀N₄O•2C₇H₈O₃S: C, 58.11; H, 5.66; N,8.74. Found: C, 57.96; H, 5.56; N, 8.69. 293 Example 288 1) RADiethyl-(2-{3-[6-(5-methyl-hexahydro- 2) S2pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]- phenoxy}-ethyl)-aminebis-fumarate ¹H NMR (300 MHz, CD₃OD) δ ppm 1.38 (t, J = 7.3 Hz, 6H),2.88 (s, 3H), 3.28 (m, 4H), 3.35 (q, J = 7.1 Hz, 4H), 3.62 (m, 6H), 3.78(m, 2H), 4.44 (dd, J = 4.8 Hz, 2H), 6.70 (s, 4H), 7.09 (ddd, J = 8.1,2.5, 0.8 Hz, 1H), 7.15 (d, J = 9.5 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H),7.54 (m, 1H), 7.65 (m, 1H), 7.91 (d, J = 9.5 Hz, 1H); MS (DCI/NH₃) m/z396 (M + H)⁺; Anal. calculated for C₂₃H₃₃N₅O•2C₄H₄O₄•NH₄OH: C, 56.18; H,7.00; N, 12.68. Found: C, 56.40; H, 6.50; N, 12.94. 294 Example 289 1)RA Diethyl-(2-{4-[6-(5-methyl-hexahydro- 2) S1pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]- phenoxy}-ethyl)-aminebis-p-toluenesulfonate ¹H NMR (300 MHz, CD₃OD) δ ppm 1.38 (t, J = 7.3Hz, 6H), 2.35 (s, 6H), 2.94 (s, 3H), 3.32 (m, 8H), 3.64 (m, 6H), 3.77(m, 2H), 4.41 (m, 2H), 7.14 (m, 3H), 7.22 (m, 4H), 7.69 (m, 4H), 7.87(d, J = 9.5 Hz, 1H), 7.93 (m, 2H); MS (DCI/NH₃) m/z 396 (M + H)⁺; Anal.calculated for C₂₃H₃₃N₅O•2C₇H₈O₃S•0.25H₂O: C, 59.70; H, 6.70; N, 9.41.Found: C, 59.41; H, 6.71; N, 9.36.

Example 295A5-[6-(4-Amino-phenyl)-pyridazin-3-yl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

The product of Example 90 (0.97 g, 3.0 mmol) and 4-aminophenylboronicacid, pinacol ester (TCl, 1.92 g, 7.5 mmol) were coupled according tothe procedure of method (G, H, I) to provide the title compound (0.91 g,2.39 mmol, 80% yield). MS (DCl/NH₃) m/z 181 (M+H)⁺.

Examples 295-300

The product of Example 295A (164 mg, 0.43 mmol) and an acylating agent(0.86 mmol) were combined in CH₂Cl₂ (2.0 mL) containing anhydrouspyridine (0.10 mL, 1.2 mmol) and stirred at rt to 40° C. for 2-18 h. Themixture was cooled to room temperature, partitioned with CH₂Cl₂ (10 mL)and 1 N aq. NaOH (5 mL) and the layers were separated. The organic layerwas washed with satd. aq. NH₄Cl (2×5 mL) and brine (5 mL), dried(Na₂SO₄) and concentrated under reduced pressure to give the acylatedproduct in 51%-84% yield. The crude materials were further processed asindicated below to provide the title compounds.

Example Acylating AgentI Conditions Resulting Compound 295Methanesulfonyl 1) EC N-{4-[6-(5-Methyl-hexahydro-pyrrolo[3,4- chloride2) S2 c]pyrrol-2-yl)-pyridazin-3-yl]-phenyl}- methanesulfonamidefumarate ¹H NMR (D₂O, 300 MHz) δ 2.89 (s, 3H) 3.07 (s, 3H) 3.22-3.56 (m,4H) 3.58-3.78 (m, 4H) 3.82-4.05 (m, 2H) 6.48 (s, 2H) 7.18 (d, J = 9.5Hz, 1H), 7.20-7.34 (m, 2H) 7.66-7.80 (m, 2H) 7.86 (d, J = 9.5 Hz, 1H);MS (DCI/NH₃) m/z 374 (M + H)⁺; Anal. C₁₈H₂₃N₅O₂S•1.0 C₄H₄O₄•2.6 H₂O: C,H, N. 296 Benzoyl chloride 1) FBN-{4-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- 2) S2pyridazin-3-yl]-phenyl}-benzamide fumarate ¹H NMR (MeOD-d₄, 300 MHz) δ3.12-3.21 (m, 2H) 3.25-3.30 (m, 2H) 3.48-3.59 (m, 2H) 3.62-3.71 (m, 2H)3.75-3.83 (m, 2H) 6.72 (s, 1H) 7.07 (d, J = 8.9 Hz, 1H) 7.48-7.55 (m,2H) 7.55-7.60 (d, J = 8.9 Hz, 1H) 7.70-7.75 (m, 2H) 7.83-7.90 (m, 2H)7.93-8.00 (m, 3H); MS (DCI/NH₃) m/z 386 (M + H)⁺; Anal. C₂₃H₂₃N₅O•0.7C₄H₄O₄: C, H, N. 297 Methanesulfonyl 1) FBN-{4-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- chloride 2) S2pyridazin-3-yl]-phenyl}-methanesulfonamide fumarate ¹H NMR (D₂O, 300MHz) δ 3.04 (s, 3H) 3.18-3.30 (m, 4H) 3.47-3.55 (m, 2H) 3.54-3.69 (m,4H) 6.41 (s, 1H) 6.95 (d, J = 9.5 Hz, 1H) 7.19-7.25 (m, 2H) 7.63 (d, J =9.8 Hz, 1H) 7.65-7.70 (m, 2H); MS (DCI/NH₃) m/z 360 (M + H)⁺; Anal.C₁₇H₂₁N₅O₂S•0.8 C₄H₄O₄: C, H, N. 298 Dimethyl sulfamoyl 1) FBN-{4-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- chloride 2) S2pyridazin-3-yl]-phenyl}- dimethylaminosulfonamide fumarate ¹H NMR (D₂O,300 MHz) δ 2.73 (s, 6H) 3.20-3.31 (m, 2H) 3.30-3.39 (m, 2H) 3.56-3.67(m, 4H) 3.76-3.87 (m, 2H) 6.49 (s, 4H) 7.17-7.25 (m, 2H) 7.29 (d, J =9.8 Hz, 1H) 7.66-7.74 (m, 2H) 7.89 (d, J = 9.8 Hz, 1H); MS (DCI/NH₃) m/z389 (M + H)⁺ 299 Acetic anhydride 1) FBN-{4-[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- 2) S4pyridazin-3-yl]-phenyl}-acetamide trifluoroacetate ¹H NMR (MeOD-d₄, 300MHz) δ 2.15 (s, 3H) 3.26-3.40 (m, 4H) 3.58-3.67 (m, 2H) 3.67-3.74 (m,2H) 3.76-3.86 (m, 2H) 7.25 (d, J = 9.6 Hz, 1H) 7.66-7.75 (m, 2H)7.86-7.95 (m, 2H) 8.00 (d, J = 9.5 Hz, 1H); MS (DCI/NH₃) m/z 324 (M +H)⁺; Anal. C₁₈H₂₁N₅O•1.3C₂HF₃O₂: C, H, N. 300 Acetic anhydride 1) FBN-{4-[6-(5-Methyl-hexahydro-pyrrolo[3,4- 2) RAc]pyrrol-2-yl)-pyridazin-3-yl]-phenyl}- 3) S4 acetamide trifluoroacetate¹H NMR (MeOD-d₄, 300 MHz) δ 2.15 (s, 3H) 2.96 (s, 3H) 3.33-3.43 (m, 4H)3.57-3.74 (m, 4H) 3.75-3.84 (m, 2H) 7.16 (d, J = 9.5 Hz, 1H) 7.65-7.72(m, 2H) 7.85-7.92 (m, 2H) 7.90 (d, J = 9.4 Hz, 1H); MS (DCI/NH₃) m/z 338(M + H)⁺; Anal. C₁₉H₂₃N₅O•C₂HF₃O₂: C, H, N.

Example 301 2-(2-Phenyl-pyrimidin-5-yl)-octahydro-pyrrolo[3,4-c]pyrroleExample 301A5-Pyrimidin-5-yl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acidtert-butyl ester

A mixture of the product of Example 6C (2.045 g, 9.63 mmol),5-bromopyrimidine (1.84 g, 11.6 mmol),tris(dibenzylideneacetone)dipalladium (0) Pd₂(dba)₃, Strem, 0.265 g,0.29 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP,Strem, 0.30 g, 0.48 mmol) and tert-BuONa (sodium tert-butoxide, 1.85 g,19.3 mmol) in 75 mL PhCH₃ was degassed three times with a N₂ back-flush.The mixture was warmed to 85° C., stirred for 48 h then was cooled,filtered and concentrated under reduced pressure. Purification by columnchromatography (SiO₂, 50% hexanes-EtOAc) gave 2.68 g of the titlecompound (9.23 mmol, 95% yield). MS (DCl/NH₃) m/z 291 (M+H)⁺.

Example 301B5-(2-Bromo-pyrimidin-5-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester

To a solution of the product of Example 301A (2.68 g, 9.23 mmol) in 75mL of CH₃CN at 0° C. was added N-bromosuccinimide (NBS, 1.64 g, 9.23mmol) in 50 mL CH₃CN portionwise via cannula. The mixture was allowed towarm to ambient temperature and stir for 16 h. The reaction mixture wasquenched by the addition of 25 mL H₂O then 50 mL CH₂Cl₂ was added. Thelayers were separated and the aqueous layer was extracted 3×20 mLCH₂Cl₂. The combined organic layers were washed with 10 mL saturated,aqueous NaCl (brine), then were dried over Na₂SO₄, and concentratedunder reduced pressure. Purification via column chromatography (SiO₂,75% hexanes-EtOAc) gave 1.2 g of the title compound (3.25 mmol, 35%yield). MS (DCl/NH₃) m/z 369, 371 (M+H)⁺.

Examples 301-304

The product of Example 301B was coupled with an aryl boronic acid andfurther processed by methods listed in the table below to provide thetitle compounds:

Example Boronic Acid Conditions Resulting Compound 301 Phenyl boronic 1)H 2-(2-Phenyl-pyrimidin-5-yl)-octahydro- acid 2) FBpyrrolo[3,4-c]pyrrole p-toluenesulfonate 3) S1 ¹H NMR (CH₃OH-d₄, 300MHz) δ 2.35 (s, 3H), 3.27 (m, 4H), 3.45 (m, 2H), 3.59 (m, 4H), 7.20 (m,2H), 7.42 (m, 3H), 7.69 (m, 2H), 8.22 (m, 2H), 8.30 (s, 2H); MS(DCI/NH₃) m/z 267 (M + H)⁺; Anal. calculated for C₁₆H₁₈N₄•1.25C₇H₈O₃S:C, 61.73; H, 5.86; N, 11.63; Found: C, 61.47; H, 5.85; N, 11.71. 302Phenyl boronic 1) H 2-Methyl-5-(2-phenyl-pyrimidin-5-yl)-octahydro- acid2) FB pyrrolo[3,4-c]pyrrole p-toluenesulfonate 3) RA ¹H NMR (CH₃OH-d₄,300 MHz) δ 2.35 (s, 3H), 2.95 (s, 3H), 4) S1 3.30 (m, 2H), 3.35 (m, 4H),3.65 (m, 4H), 7.21 (m, 2H), 7.43 (m, 3H), 7.69 (m, 2H), 8.23 (m, 2H),8.36 (s, 2H); MS (DCI/NH₃) m/z 281 (M + H)⁺; Anal. calculated forC₁₇H₂₀N₄•C₇H₈O₃S: C, 63.69; H, 6.24; N, 12.38; Found: C, 63.32; H, 6.12;N, 12.07. 303 o-methoxyphenyl 1) H2-[5-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)- boronic acid 2) DeMepyrimidin-2-yl]-phenol p-toluenesulfonate 3) FB ¹H NMR (300 MHz, CD₃OD)δ ppm 0.93 (m, 1H), 1.35 (m, 4) S1 1H), 2.35 (s, 3H), 3.30 (m, 2H), 3.56(m, 6H), 6.91 (m, 2H), 7.22 (m, 2H), 7.28 (ddd, J = 8.1, 7.1, 1.7 Hz,1H), 7.69 (m, 2H), 8.30 (dd, J = 8.1, 1.7 Hz, 1H), 8.37 (s, 2H); MS(DCI/NH₃) m/z 283 (M + H)⁺; Anal. calculated forC₁₆H₁₈N₄O•1.5C₇H₈O₃S•H₂O: C, 56.97; H, 5.77; N, 10.03. Found: C, 57.04;H, 5.44; N, 10.30. 304 o-methoxyphenyl 1) H2-[5-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2- boronic acid 2) DeMeyl)-pyrimidin-2-yl]-phenol p-toluenesulfonate ¹H 3) FB NMR (300 MHz,CD₃OD) □ ppm 2.35 (s, 3H), 2.95 (s, 3H), 4) RA 3.28 (m, 4H), 3.37 (m,3H), 3.67 (m, 3H), 6.89 (m, 2H), 5) S1 7.22 (m, 2H), 7.27 (dd, J = 7.5,1.7 Hz, 1H), 7.69 (m, 2H), 8.30 (dd, J = 8.3, 1.9 Hz, 1H), 8.40 (s, 2H);MS (DCI/NH₃) m/z 297 (M + H)⁺; Anal. calculated forC₁₆H₁₈N₄O•C₇H₈O₃S•0.25H₂O: C, 60.93; H, 6.07; N, 11.84. Found: C, 60.84;H, 5.98; N, 11.58.

Example 3055-(4-Bromo-phenyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acidtert-butyl ester

The product of Example 6C (0.75 g, 3.53 mmol), 1,4-dibromobenzene (0.83g, 3.53 mmol), tris(dibenzylideneacetone)dipalladium (0) (Pd₂(dba)₃,Strem, 65 mg, 0.071 mmol),racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BiNAP, Strem, 88mg, 0.14 mmol), and NaOt-Bu (0.54 g, 5.6 mmol) were combined in toluene(15 mL). This mixture was stirred at 100° C. for 24 h. The reactionmixture was cooled to ambient temperature, filtered, concentrated underreduced pressure and purified by column chromatography (SiO₂, 70%hexanes in EtOAc) to give the title compound (0.65 g, 1.8 mmol, 50%yield). MS (DCl/NH₃) m/z 367 (M+H)⁺.

Examples 306-309

The intermediate Example 305 was coupled with an aryl boronic acid andfurther processed by methods listed to provide the title compounds:

Example Boronic Acid Conditions Resulting Compound 306 3-pyridinyl 1) G2-(4-Pyridin-3-yl-phenyl)-octahydro-pyrrolo[3,4- boronic acid 2) FBc]pyrrole bis-trifluoroacetate ¹H NMR (300 MHz, 3) S4 CD₃OD) δ ppm 3.25(m, 4H), 3.45 (m, 2H), 3.53 (m, 2H), 3.63 (m, 2H), 6.89 (m, 2H), 7.67(m, 2H), 7.86 (dd, J = 8.1, 5.4 Hz, 1H), 8.56 (m, 2H), 8.95 (s, 1H); MS(DCI/NH₃) m/z 266 (M + H)⁺; Anal. calculated forC₁₇H₁₉N₃•2CF₃CO₂H•0.5H₂O: C, 50.20; H, 4.41; N, 8.38. Found: C, 50.51;H, 4.29; N, 8.12. 307 3-pyridinyl 1) G2-Methyl-5-(4-pyridin-3-yl-phenyl)-octahydro- boronic acid 2) FBpyrrolo[3,4-c]pyrrole p-toluenesulfonate ¹H NMR 3) RA (300 MHz, CD₃OD) δppm 2.36 (s, 3H), 2.93 (s, 3H), 4) S1 3.23 (m, 4H), 3.38 (m, 2H), 3.59(m, 3H), 3.99 (m, J = 7.5 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 7.22 (m,2H), 7.69 (m, 4H), 7.89 (m, 1H), 8.59 (d, J = 5.8 Hz, 2H), 8.97 (s, 1H);MS (DCI/NH₃) m/z 280 (M + H)⁺; Anal. calculated for C₁₈H₂₁N₃•1.8C₇H₈O₃S:C, 62.36; H, 6.05; N, 7.13. Found: C, 62.32; H, 6.01; N, 7.13. 308Phenyl boronic 1) H 2-Biphenyl-4-yl-octahydro-pyrrolo[3,4-c]pyrrole acid2) FB trifluoroacetate 3) S4 ¹H NMR (300 MHz, CD₃OD) δ ppm 3.29 (m, 6H),3.52 (d, J = 8.8 Hz, 2H), 3.61 (m, 2H), 6.83 (m, 2H), 7.23 (m, 1H), 7.37(m, 2H), 7.52 (m, 4H); MS (DCI/NH₃) m/z 265 (M + H)⁺; Anal. calculatedfor C₁₈H₂₀N₂•CF₃CO₂H•0.2H₂O: C, 62.89; H, 5.65; N, 7.33. Found: C,62.84; H, 5.41; N, 7.11. 309 Phenyl boronic 1) H2-Biphenyl-4-yl-5-methyl-octahydro-pyrrolo[3,4- acid 2) FB c]pyrrolehydrochloride ¹H NMR (300 MHz, CD₃OD) δ 3) RA ppm 2.92 (s, 3H), 3.21 (m,2H), 3.40 (m, 4H), 3.64 (m, 3H), 4) S3 3.98 (m, 1H), 6.96 (m, 2H), 7.25(t, J = 7.8 Hz, 1H), 7.38 (t, J = 7.6 Hz, 2H), 7.54 (m, 4H); MS(DCI/NH₃) m/z 279 (M + H)⁺; Anal. calculated for C₁₉H₂₂N₂•HCl: C, 64.96;H, 6.89; N, 7.97. Found: C, 64.68; H, 7.08; N, 7.76.

Example 3101-Methyl-5-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-1H-indoleFumarate

The product of Example 115 was converted to the free base by method FB.This material was subjected to indole N-methylation according to theprocedure of Method RA, followed by salt formation according to methodS2 to provide the title compound: ¹H NMR (CH₃OH-d₄, 300 MHz) δ 2.87 (s,3H), 3.19-3.39 (m, 4H), 3.52-3.68 (m, 4H), 3.73-3.81 (m, 2H), 3.84 (s,3H), 6.53 (d, J=3.1 Hz, 1H), 6.68 (s, 2H), 7.16 (d, J=9.5 Hz, 1H), 7.22(d, J=3.1 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.79 (dd, J=8.8, 1.7 Hz, 1H),7.94 (d, J=9.5 Hz, 1H), 8.10 ppm (d, J=1.4 Hz, 1H); MS (DCl/NH₃) m/z 334(M+H)⁺; Anal. C₂₀H₂₃N₅.1.14C₄H₄O₄: C, H, N.

Example 311Dimethyl-{5-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-1H-indol-3-ylmethyl}-aminefumarate

The product of Example 115 was converted to the free base by method FB.The free base (90 mg, 0.28 mmol), 37% formaldehyde solution (34 mg, 0.42mmol) and 2M dimethylamine solution in THF (0.21 ml, 0.42 mmol) werecombined in dioxane (1 mL) and HOAc (1 mL), and the mixture was stirredat room temperature for 4 h. The mixture was concentrated, and theresidue was purified by preparative HPLC (Xterra® column,NH₄HCO₃—CH₃CN). The product was converted to the title compoundaccording to method S2 (81 mg, 50% yield): ¹H NMR (CH₃OH-d₄, 300 MHz) δppm 2.78-2.85 (m, 9H), 3.32-3.41 (m, 4H), 3.42-3.49 (m, 2H), 3.61 (dd,J=10.8, 6.9 Hz, 2H), 3.84 (d, J=11.9 Hz, 2H), 4.50 (s, 2H), 6.52 (s,3H), 7.08 (d, J=9.5 Hz, 1H), 7.49-7.57 (m, 2H), 7.78 (dd, J=8.7, 1.4 Hz,1H), 7.85 (d, J=9.5 Hz, 1H), 8.22 (s, 1H); MS (DCl/NH₃) m/z 377 (M+H)⁺;Anal. C₂₂H₂₈N₆.1.6C₄H₄O₄.H₂O: C, H, N.

Example 312(1S,5S)-6-[6-(6-Methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridazin-3-yl]-2,3,4,9-tetrahydro-1H-carbazoleBis(trifluoroacetate) Example 312AN-{4-[6-(6-Methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridazin-3-yl]-phenyl}-hydrazinecarboxylicacid tert-butyl ester

The free base of the product of Example 85 (790 mg, 2 mmol), tert-butylcarbazate (317 mg, 2.4 mmol), cesium carbonate (910 mg, 2.8 mmol) andCuI (29 mg, 0.15 mmol) were combined in DMF (8 mL). The mixture wasstirred at 80° C. under N₂ for 16 hours. The reaction mixture waspurified via column chromatography (SiO₂, 10% CH₂Cl₂-MeOH) to give 0.6 gof the title compound (1.5 mol, 75% yield). ¹H NMR (300 MHz, CD₃OD) δ1.52 (s, 9H), 2.41 (s, 3H), 3.18-3.41 (m, 4H), 3.59 (dd, J=11.4, 8.3 Hz,1H), 3.94-4.03 (m, 2H), 4.06 (dd, J=6.8, 4.4 Hz, 1H), 7.15 (d, J=9.5 Hz,1H), 7.58 (d, J=8.8 Hz, 2H), 7.85-7.94 ppm (m, J=9.2, 7.1 Hz, 3H); MS(DCl/NH₃) m/z 397 (M+H)⁺.

Example 312B6-[6-(6-Methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridazin-3-yl]-2,3,4,9-tetrahydro-1H-carbazolebis(trifluoroacetate)

The product of Example 312A (200 mg, 0.5 mmol), cyclohexanone (98 mg, 1mmol) and p-toluenesulfonic acid (30 mg, 0.15 mmol) were combined inEtOH (3 mL), and the mixture was heated in the microwave reactor to 150°C. for 10 minutes. The crude reaction mixture was purified bypreparative HPLC (Xterra® column, 0.1% TFA-CH₃CN), to provide the titlecompound (19.9 mg, 6% yield). 1H NMR (300 MHz, CD₃OD) δ 1.85-2.01 (m,4H), 2.72-2.82 (m, 5H), 2.96-3.09 (m, 2H), 3.43-3.70 (m, 4H), 4.06-4.28(m, 2H), 4.52-4.64 (m, 1H), 4.95-5.09 (m, 1H), 7.46 (d, J=8.5 Hz, 1H),7.60 (dd, J=8.5, 2.0 Hz, 1H), 7.80 (d, J=9.8 Hz, 1H), 8.00 (d, J=1.7 Hz,1H), 8.42 ppm (d, J=9.8 Hz, 1H); MS (DCl/NH₃) m/z 360 (M+H)⁺; Anal.calculated for C₂₂H₂₅N₅.2.5C₂F₃HO₂.0.3H₂O: C, 49.90; H, 4.36; N, 10.78.Found: C, 49.85; H, 4.51; N, 10.89.

Example 314 2-(5-Phenyl-1H-pyrazol-3-yl)-2,5-diaza-bicyclo[2.2.1]heptanebis-p-toluenesulfonate Example 314A5-(1-Methylsulfanyl-3-oxo-3-phenyl-propenyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

3,3-Bis-methylsulfanyl-1-phenyl-propenone (0.675 g, 3.0 mmol), wasprepared according to literature procedure (Galli, f. et al WO 01/92251A1) and was combined with the product of Example 24 (0.200 g, 1.0 mmol)in 10 mL MeOH. This mixture was warmed to 70° C. for 4 h then was cooledto ambient temperature, concentrated under reduced pressure and purifiedvia column chromatography (SiO₂, 10% CH₃OH—CH₂Cl₂ with 1% NH₄OH) to give0.159 g of the title compound (0.38 mmol, 38% yield). MS (DCl/NH₃) m/z375 (M+H)⁺.

Example 314B5-(5-Phenyl-1H-pyrazol-3-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

The product of example 314B (0.143 g, 0.42 mmol), hydrazine 1.0Msolution in THF (1.7 mL, 1.7 mmol), sodium acetate (0.13 g, 1.3 mmol)were combined in toluene (4 mL), acetic acid (2 mL), water (0.5 mL), andethanol. The mixture was heated to reflux for 8 h. The mixture waspoured into saturated Aq sodium carbonate and extracted with EtOAc theorganics were dried over MgSO₄ and concentrated under reduced pressure.The residue was purified by column chromatography (SiO₂, 10%CH₃OH—CH₂Cl₂ with 1% NH₄OH) to provide the title compound (0.088 g, 0.24mmol, 57% yield). MS (DCl/NH₃) m/z 356 (M+H)⁺.

Example 314C2-(5-Phenyl-1H-pyrazol-3-yl)-2,5-diaza-bicyclo[2.2.1]heptanebis-p-toluenesulfonate

The product of Example 314B was processed according to method FB, and S1to provide the title salt. 1H NMR (CH₃OH-d₄, (300 MHz) δ 2.04-2.20 (m,2H) 2.26-2.42 (m, 6H) 3.35-3.44 (m, 1H) 3.45-3.66 (m, 2H) 3.66-3.86 (m,1H) 4.49-4.72 (m, 2H) 6.28-6.47 (m, 1H) 7.14-7.30 (m, 5H) 7.45-7.59 (m,1H) 7.62-7.83 ppm (m, 7H). MS (DCl/NH₃) m/z 241 (M+H)⁺. Anal. calculatedfor C₁₄H₁₆N₄.2.C₇H₈O₃S.0: C, 57.51; H, 5.52; N, 9.58. Found: C, 57.39;H, 5.19; N, 9.14

Example 315 Example 315A Benzyl(1S,5S)-6-(5-cyano-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate

The product of Example 7J (830 mg, 3.58 mmol) in toluene (20 mL) wastreated with Pd₂(dba)₃ (71.0 mg, 0.072 mmol), BINAP (134 mg, 0.214mmol), Cs₂CO₃ (2.32 g, 7.16 mmol) and 3-bromo-5-cyanopyridine (0.98 g,5.37 mmol). The mixture was heated at 100° C. under N₂ for 10 hours andthen allowed to cool to room temperature and diluted with ethyl acetate(100 mL). The brown solution was washed with water (2×10 mL) andconcentrated under reduced pressure. The residue was purified bychromatography (SiO₂, EtOAc:hexane, 50:50, R_(f) 0.3) to provide thetitle compound (770 mg, 64% yield). ¹H NMR (MeOH-d₄, 300 MHz) δ 3.2 (dd,J=12.9, 4.Hz, 1H), 3.30-3.4 (m, 2H), 3.6 (dd, J=8.2, 3.Hz, 1H),3.96-4.10 (m, 3H), 4.74 (dd, J=6.1, 4.0 Hz, 1H), 5.10 (m, 2H), 7.15 (dd,J=2.7, 1.7 Hz, 1H), 7.25 (m, 3H), 7.35 (m, 2H), 7.96 (d, J=2.7 Hz, 1H),8.15 (d, J=1.7 Hz, 1H); MS (DCl/NH₃) m/z 335 (M+H)⁺.

Example 315B Benzyl(1S,5S)-6-(6-bromo-5-cyano-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate

The product of Example 315A was treated with N-bromosuccinimide inacetonitrile according to the method of Example 301B to provide thetitle compound: MS (DCl/NH₃) m/z 413/415 (M+H)⁺.

Example 315C Benzyl(1S,5S)-6-(6-[2-thienyl]-5-cyano-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate

The product of Example 315B was coupled with 2-thienyl boronic acidaccording to the procedure of method I to provide the title compound: MS(DCl/NH₃) m/z 417 (M+H)⁺.

Example 315D(1R,5S)-5-(3,6-Diaza-bicyclo[3.2.0]hept-6-yl)-2-thiophen-2-yl-nicotinonitriletrifluoroacetate

The product of Example 315C was stirred in trifluoroacetic acid at 65°C. for 2 h, then cooled to room temperature and concentrated undervacuum. The residue was triturated with 10% methanol in ether to providethe title compound:

¹H NMR (MeOH-D₄, 300 MHz) □ 3.20 (dd, J=12.9, 3.8 Hz, 1H), 3.33-3.42 (m,1H), 3.41-3.61 (m, 1H), 3.66-3.89 (m, 3H), 4.13 (t, J=8.1 Hz, 1H), 5.01(dd, J=6.6, 3.6 Hz, 1H), 7.14 (dd, J=5.1, 3.7 Hz, 1H), 7.36 (d, J=2.7Hz, 1H), 7.53 (d, J=5.1 Hz, 1H), 7.95 (d, J=3.7 Hz, 1H), 8.10 (d, J=3.1Hz, 1H); MS (DCl/NH₃) m/z 283 (M+H)⁺; Anal. Calculated forC₁₅H₁₄N₄S.1.12CF₃CO₂H.1.90H₂O: C, 54.08; H, 5.64; N, 9.83. Found: C,54.33; H, 5.30; N, 9.46.

Example 316(1R,5S)-5-(3-Methyl-3,6-diaza-bicyclo[3.2.0]hept-6-yl)-2-thiophen-2-yl-nicotinonitrilefumarate

The product of Example 315D was processed according to method RA, thenconverted to the salt according to method S2: ¹H NMR (MeOH-D₄, 300 MHz)δ 2.82-2.93 (m, 4H), 3.00 (dd, J=11.7, 7.0 Hz, 1H), 3.39-3.58 (m, 1H),3.73 (d, J=11.9 Hz, 1H), 3.77-3.91 (m, 2H), 4.10 (t, J=8.1 Hz, 1H), 4.96(dd, J=6.8, 3.4 Hz, 1H), 6.69 (s, 2H), 7.13 (dd, J=5.1, 3.7 Hz, 1H),7.30 (d, J=2.7 Hz, 1H), 7.52 (d, J=5.1 Hz, 1H), 7.93 (d, J=3.7 Hz, 1H),8.07 (d, J=3.1 Hz, 1H); MS (DCl/NH₃) m/z 297 (M+H)⁺; Anal. Calculatedfor C₁₆H₁₆N₄S.1.10 C₄H₄O₄.1.10H₂O: C, 62.26; H, 6.25; N, 10.18. Found:C, 62.34; H, 6.31; N, 10.43.

Example 318(1S,5S)-3-(4-Pyridin-3-yl-phenyl)-3,6-diaza-bicyclo[3.2.0]heptanebis(p-toluenesulfonate) Example 318A(1S,5R)-3-(4-bromophenyl)-3,6-diaza-bicyclo[3.2.0]heptane-6-carboxylatet-butyl ester

The product of Example 8B was coupled with p-dibromobenzene according tothe procedure of Example 128A to provide the title compound.

Example 318B(1S,5S)-3-(4-Pyridin-3-yl-phenyl)-3,6-diaza-bicyclo[3.2.0]heptanebis(p-toluenesulfonate)

The product of Example 318A was coupled with pyridine-3-boronic acidaccording to the procedure of Method I. The product was furtherprocessed according to method FB and method S1 to provide the titlecompound: ¹H NMR (MeOH-D₄, 300 MHz) δ 2.37 (s, 6H) 3.02 (dd, J=10.5, 6.1Hz, 1H), 3.10 (dd, J=12.5, 4.7 Hz, 1H), 3.39-3.60 (m, 1H), 3.75 (dd,J=11.0, 5.3 Hz, 1H), 3.93 (d, J=10.9 Hz, 1H), 4.14 (d, J=12.5 Hz, 1H),4.25 (dd, J=10.8, 8.5 Hz, 1H), 5.02 (dd, J=7.0, 4.9 Hz, 1H), 6.93-7.16(m, 2H) 7.23 (d, J=8.1 Hz, 4H) 7.47 (dd, J=8.0, 4.9 Hz, 1H) 7.56-7.66(m, 3H) 7.64-7.80 (m, 4H) 7.95-8.15 (m, 1H) 8.44 (dd, J=4.9, 1.5 Hz, 1H)8.75 (d, J=1.7 Hz, 1H); MS (DCl/NH₃) m/z 252 (M+H)⁺; Anal. Calculatedfor C₁₆H₁₇N₃.2.20 C₇H₈SO₃.0.50H₂O: C, 59.00; H, 5.61; N, 6.57. Found: C,58.75; H, 5.72; N, 6.75.

Example 319(1S,5S)-6-Methyl-3-(4-pyridin-3-yl-phenyl)-3,6-diaza-bicyclo[3.2.0]heptanebis(p-toluenesulfonate)

The product of Example 318A was coupled with pyridine-3-boronic acidaccording to method I, and further processed according to methods FB,RA, and S1 to provide the title compound: ¹H NMR (MeOH-D₄, 300 MHz) δ2.39 (S, 6H), 2.89-2.90 (m, 4H), 3.11 (dd, J=13.2, 4.7 Hz, 1H),3.38-3.62 (m, 1H), 3.94 (d, J=9.8 Hz, 1H), 4.01-4.16 (m, 2H), 4.16-4.34(m, 1H), 4.72-5.05 (m, 1H), 7.08 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.1 Hz,4H), 7.51-7.91 (m, 6H) 8.35 (d, J=8.1 Hz, 1H), 8.55 (d, J=3.7 Hz, 1H),8.89 (s (br.), 1H); MS (DCl/NH₃) m/z 266 (M+H)⁺; Anal. Calculated forC₁₇H₁₉N₃.2.00 C₇H₈SO₃.0.60H₂O: C, 60.00; H, 5.88; N, 6.77. Found: C,59.92; H, 5.72; N, 6.74.

Example 320(1S,5S)-5-[4-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)-phenyl]-3-methyl-1H-indazolebis(p-toluenesulfonate)

The product of Example 318A was coupled with the product of Example 212Aaccording to the procedure of Example 212B. The product was furtherprocessed according to methods FB and S1 to provide the title compound:¹H NMR (MeOH-D₄, 300 MHz) δ 2.28 (s, 6H), 2.53 (s, 3H), 2.59 (d, J=9.8Hz, 1H), 2.91 (dd, J=10.3, 5.9 Hz, 1H), 3.02 (dd, J=11.7, 4.9 Hz, 1H),3.33-3.44 (m, 1H), 3.89 (d, J=10.5 Hz, 1H), 4.04-4.21 (m, 2H), 4.87-5.05(m, J=4.7 Hz, 1H), 6.96 (d, J=8.5 Hz, 2H), 7.10 (d, J=7.8 Hz, 4H),7.41-7.54 (m, 5H), 7.56-7.69 (m, 3H), 7.90 (s, 1H); MS (DCl/NH₃) m/z 305(M+H)⁺; Anal. Calculated for C₁₉H₂₀N₄.2.00 C₇H₈SO₃.0.60H₂O: C, 59.84; H,5.60; N, 8.46. Found: C, 60.04; H, 5.72; N, 8.70.

Example 321 Determination of Biological Activity

To determine the effectiveness of representative compounds of thisinvention as α7 nAChRs, the compounds of the invention were evaluatedaccording to the [3H]-methyllycaconitine (MLA) binding assay andconsidering the [3H]-cytisine binding assay, which were performed asdescribed below.

[3H]-Cytisine Binding

Binding conditions were modified from the procedures described inPabreza L A, Dhawan, S, Kellar K J, [³H]-Cytisine Binding to NicotinicCholinergic Receptors in Brain, Mol. Pharm. 39: 9-12, 1991. Membraneenriched fractions from rat brain minus cerebellum (ABS Inc.,Wilmington, Del.) were slowly thawed at 4° C., washed and resuspended in30 volumes of BSS-Tris buffer (120 mM NaCl/5 mM KCl/2 mM CaCl₂/2 mMMgCl₂/50 mM Tris-Cl, pH 7.4, 4° C.). Samples containing 100-200 μg ofprotein and 0.75 nM [3H]-cytisine (30 C_(i)/mmol; Perkin Elmer/NEN LifeScience Products, Boston, Mass.) were incubated in a final volume of 500μL for 75 minutes at 4° C. Seven log-dilution concentrations of eachcompound were tested in duplicate. Non-specific binding was determinedin the presence of 10 μM (−)-nicotine. Bound radioactivity was isolatedby vacuum filtration onto prewetted glass fiber filter plates(Millipore, Bedford, Mass.) using a 96-well filtration apparatus(Packard Instruments, Meriden, Conn.) and were then rapidly rinsed with2 mL of ice-cold BSS buffer (120 mM NaCl/5 mM KCl/2 mM CaCl₂/2 mMMgCl₂). Packard MicroScint-20® scintillation cocktail (40 μL) was addedto each well and radioactivity determined using a Packard TopCount®instrument. The IC₅₀ values were determined by nonlinear regression inMicrosoft Excel® software. K_(i) values were calculated from the IC₅₀susing the Cheng-Prusoff equation, where K_(i)=IC₅₀/1+[Ligand]/K_(D)].

[3H]-Methylycaconitine (MLA) Binding

Binding conditions were similar to those for [3H]-cytisine binding.Membrane enriched fractions from rat brain minus cerebellum (ABS Inc.,Wilmington, Del.) were slowly thawed at 4° C., washed and resuspended in30 volumes of BSS-Tris buffer (120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 2 mMMgCl₂, and 50 mM Tris-Cl, pH 7.4, 22° C.). Samples containing 100-200 μgof protein, 5 nM [3H]-MLA (25 C_(i)/mmol; Perkin Elmer/NEN Life ScienceProducts, Boston, Mass.) and 0.1% bovine serum albumin (BSA, Millipore,Bedford, Mass.) were incubated in a final volume of 500 μL for 60minutes at 22° C. Seven log-dilution concentrations of each compoundwere tested in duplicate. Non-specific binding was determined in thepresence of 10 μM MLA. Bound radioactivity was isolated by vacuumfiltration onto glass fiber filter plates prewetted with 2% BSA using a96-well filtration apparatus (Packard Instruments, Meriden, Conn.) andwere then rapidly rinsed with 2 mL of ice-cold BSS. PackardMicroScint-20® scintillation cocktail (40 μL) was added to each well andradioactivity was determined using a Packard TopCount® instrument. TheIC₅₀ values were determined by nonlinear regression in Microsoft Excel®software. K_(i) values were calculated from the IC₅₀s using theCheng-Prusoff equation, where K_(i)=IC₅₀/1+[Ligand]/K_(D)].

Compounds of the invention had K_(i) values of from about 1 nanomolar toabout 10 micromolar when tested by the MLA assay, many having a K_(i) ofless than 1 micromolar. [3H]-Cytisine binding values of compounds of theinvention ranged from about 50 nanomolar to at least 100 micromolar. Thedetermination of preferred compounds typically considered the K_(i)value as measured by MLA assay in view of the K_(i) value as measured by[3H]-cytisine binding, such that in the formulaD=K_(i MLA)/K_(i 3H-cytisine), D is about 50. Preferred compoundstypically exhibited greater potency at α7 receptors compared to α4β2receptors.

Compounds of the invention are α7 nAChRs ligands that modulate functionof α7 nAChRs by altering the activity of the receptor. The compounds canbe inverse agonists that inhibit the basal activity of the receptor orantagonists that completely block the action of receptor-activatingagonists. The compounds also can be partial agonists that partiallyblock or partially activate the α7 nAChR receptor or agonists thatactivate the receptor.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof.

What is claimed is:
 1. A compound of the formula (I):Z-Ar₁—Ar₂  (I) wherein: Z is a diazabicyclic amine of formula:

Ar₁ is a pyridine ring of formula:

wherein, only one of X₁, X₂, X₃, and X₄ is N and the remaining are —CR₃;Ar₂ is selected from the group consisting of 5- or 6-memberedheteroaryl, bicyclic heteroaryl, 3,4-(methylenedioxy)phenyl, carbazolyl,tetrahydrocarbazolyl, naphthyl, and phenyl, substituted with 0, 1, 2, or3 substituents selected from the group consisting of alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl,alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio,alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen,hydroxy, hydroxyalkyl, mercapto, nitro, —NR_(A)R_(B),(NR_(A)R_(B))alkyl, (NR_(A)R_(B))carbonyl, (NR_(A)R_(B))sulfonyl, andphenyl; l, m, o, and p are each independently 0, 1, or 2, and n is 0,provided that the sum total of l, m, n, o, and p is 3, 4, or 5, andfurther provided that the sum of l and o is at least 1 and the sum of mand p is at least 1; R₁ is selected from the group consisting ofhydrogen, alkenyl, alkyl alkoxycarbonyl, arylalkyl, and heteroarylalkyl;R₂ at each occurrence is independently selected from the groupconsisting of hydrogen, alkoxycarbonyl, and alkyl; R₃ at each occurrenceis independently selected from the group consisting of hydrogen, alkoxy,alkyl, cyano, and hydroxy; R_(A) and R_(B) are each independentlyselected from the group consisting of hydrogen, alkyl, alkylcarbonyl,alkylsulfonyl, arylcarbonyl, formyl and (NR_(C)R_(D))sulfonyl; and R_(C)and R_(D) are each independently selected from the group consisting ofhydrogen and alkyl; or a pharmaceutically acceptable salt, ester, oramide thereof.
 2. The compound as in claim 1, wherein Z is thediazabicyclic amine selected from the group consisting of:

or a pharmaceutically acceptable salt, ester, or amide thereof.
 3. Thecompound of claim 1, wherein Ar₂ is selected from the group consistingof benzofuranyl; benzothienyl; carbazolyl; tetrahydrocarbazolyl; furyl;imidazolyl; 3-indolyl; 4-indolyl; 5-indolyl; isoxazolyl; naphthyl;pyrazolyl; pyridazinyl; pyridyl; pyrimidinyl; 2-pyrrolyl, 3-pyrrolyl;quinolinyl; thienyl; 3,4-(methylenedioxy)phenyl; and phenyl; wherein thephenyl is substituted with 0, 1, or 2 substituents selected from thegroup consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl,carboxy, cyano, halogen, haloalkoxy, haloalkyl, hydroxy, nitro,—NR_(A)R_(B), (NR_(A)R_(B))alkyl, (NR_(A)R_(B))alkoxy, and phenyl; or apharmaceutically acceptable salt, ester, or amide thereof.
 4. Thecompound of claim 1, wherein Ar₂ is selected from the group consistingof:

wherein R₄ at each occurrence is independently selected from the groupconsisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl,carboxy, cyano, halogen, haloalkoxy, haloalkyl, hydroxy, nitro,—NR_(A)R_(B), (NR_(A)R_(B))alkyl, (NR_(A)R_(B))alkoxy, and phenyl; or apharmaceutically acceptable salt, ester, or amide thereof.
 5. Thecompound of claim 1, wherein Ar₂ is selected from the group consistingof phenyl, para-acetylaminophenyl, meta-aminophenyl, para-aminophenyl,para(2-(diethylamino)ethoxy)phenyl, meta(2-(diethylamino)ethoxy)phenyl,para-(dimethylamino)phenyl, para-bromophenyl, meta-cyanophenyl,para-cyanophenyl, meta-hydroxyphenyl, para-hydroxyphenyl,para-iodophenyl, meta-methylphenyl, para-methylphenyl,3,5-dimethylphenyl, meta-methoxyphenyl, para-methoxyphenyl,meta-trifluoromethoxyphenyl, meta-nitrophenyl, para-nitrophenyl, andmeta-trifluoromethylphenyl; or a pharmaceutically acceptable salt,ester, or amide thereof.
 6. The compound of claim 1, wherein Z is

or a pharmaceutically acceptable salt, ester, or amide thereof.
 7. Thecompound of claim 6, wherein Ar₂ is selected from the group consistingof 3-indolyl, 5-indolyl; 1-methyl-3-indolyl, 1-methyl-5-indolyl,3-methyl-5-indolyl, 3,4-(methylenedioxy)phenyl, and phenyl, wherein Ar₂is substituted with 0, 1, or 2 substituents selected from the groupconsisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy,cyano, halogen, haloalkoxy, haloalkyl, hydroxy, nitro, —NR_(A)R_(B),(NR_(A)R_(B))alkyl, (NR_(A)R_(B))alkoxy, and phenyl; or apharmaceutically acceptable salt, ester, or amide thereof.
 8. Thecompound of claim 6, wherein Z is

Ar₂ is selected from the group consisting of heteroaryl and bicyclicheteroaryl, provided that Ar₂ is not 1-pyrrolyl or 1-indolyl; or apharmaceutically acceptable salt, ester, or amide thereof.
 9. Thecompound of claim 1, selected from the group consisting of:2-(6-Phenyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;2-(6-o-Tolyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;2-(6-m-Tolyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;2-(6-biphenyl-3-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;2-(6-biphenyl-3-yl-pyridin-3-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;2-[6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole;2-methyl-5-[6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole;3-[5-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-2-yl]-phenylamine;5-(6-furan-3-yl-pyridin-3-yl)-hexahydro-pyrrolo[3,4-c]pyrrole;2-(6-furan-3-yl-pyridin-3-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;2-(6-benzo[b]thiophen-2-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;2-(6-benzo[b]thiophen-2-yl-pyridin-3-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;2-(5-phenyl-pyridin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole;2-methyl-5-(5-phenyl-pyridin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole;(1R,5R)-1-{4-[5-(3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-phenyl}-ethanone;(1R,5R)-1-{4-[5-(6-methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-phenyl}-ethanone;6a-methyl-5-(6-m-tolyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-b]pyrrole;2-methyl-5-(5-pyrimidin-5-yl-pyridin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole;2-methyl-5-[5-(1H-pyrazol-4-yl)-pyridin-2-yl]-octahydro-pyrrolo[3,4-c]pyrrole;3-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-3-yl]-benzonitrile;2-[5-(2-methoxy-pyrimidin-5-yl)-pyridin-2-yl]-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;2-[5-(3,5-dimethyl-1H-pyrazol-4-yl)-pyridin-2-yl]-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;2-methyl-5-[5-(1-methyl-1H-pyrazol-4-yl)-pyridin-2-yl]-octahydro-pyrrolo[3,4-c]pyrrole;2-[5-(3,5-dimethyl-isoxazol-4-yl)-pyridin-2-yl]-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-[3,3′]bipyridinyl;6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-[3,4′]bipyridinyl;4-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-3-yl]-benzonitrile;6′-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-[3,3′]bipyridinyl-6-ylamine;2-methyl-5-[5-(1H-pyrrol-3-yl)-pyridin-2-yl]-octahydro-pyrrolo[3,4-c]pyrrole;2-methyl-5-[5-(1H-pyrrol-2-yl)-pyridin-2-yl]-octahydro-pyrrolo[3,4-c]pyrrole;6′-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-[3,3′]bipyridinyl-2-carbonitrile;2-(5-furan-3-yl-pyridin-2-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;2-methyl-5-(5-thiophen-2-yl-pyridin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole;2-methyl-5-(5-thiophen-3-yl-pyridin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole;2-(5-benzofuran-5-yl-pyridin-2-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;2-(5-furan-2-yl-pyridin-2-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;3-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-3-yl]-9H-carbazole;5-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-3-yl]-1H-indole;4-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-3-yl]-1H-indole;2-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-3-yl]-2H-pyridazin-3-one;2-[6-(3-methoxy-phenyl)-pyridin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole2-[6-(3-trifluoromethoxy-phenyl)-pyridin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole;2-(6-thiophen-3-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;8-[5-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-2-yl]-quinoline;2-(6-naphthalen-2-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;2-(6-benzofuran-2-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;2-methyl-5-(6-o-tolyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;2-methyl-5-(6-m-tolyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;2-methyl-5-(6-phenyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;2-[6-(3-methoxy-phenyl)-pyridin-3-yl]-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole;2-methyl-5-[6-(3-trifluoromethoxy-phenyl)-pyridin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole;2-methyl-5-[6-(3-nitro-phenyl)-pyridin-3-yl]-octahydro-pyrrolo[3,4-c]pyrrole;2-methyl-5-(6-thiophen-3-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;8-[5-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-2-yl]-quinoline;2-methyl-5-(6-naphthalen-2-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole;5-[5-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-2-yl]-1H-indole;4-[5-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-2-yl]-1H-indole;5-[5-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-2-yl]-quinoline;(1S,5S)-5-[6-(3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-3-yl]-3-methyl-1H-indazole;(1R,5R)-{4-[5-(3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-phenyl}-dimethyl-amine;(1R,5R)-6-methyl-3-(6-m-tolyl-pyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;(1R,5R)-6-methyl-3-(6-p-tolyl-pyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;(1R,5R)-3-[5-(6-methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-benzonitrile;(1R,5R)-3-[6-(4-ethyl-phenyl)-pyridin-3-yl]-6-methyl-3,6-diaza-bicyclo[3.2.0]heptane;(1R,5R)-dimethyl-{4-[5-(6-methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-phenyl}-amine;(1R,5R)-3-[6-(3-methoxy-phenyl)-pyridin-3-yl]-6-methyl-3,6-diaza-bicyclo[3.2.0]heptane;(1R,5R)-3-(6-benzo[1,3]dioxol-5-yl-pyridin-3-yl)-6-methyl-3,6-diaza-bicyclo[3.2.0]heptane;(1R,5R)-3-[6-(4-methoxy-phenyl)-pyridin-3-yl]-6-methyl-3,6-diaza-bicyclo[3.2.0]heptane;(1R,5R)-3-[6-(3,4-dimethoxy-phenyl)-pyridin-3-yl]-6-methyl-3,6-diaza-bicyclo[3.2.0]heptane;(1R,5R)-6-methyl-3-(6-phenyl-pyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;(1R,5R)-5-(6-methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-[2,3′]bipyridinyl;(1R,5R)-5-[5-(6-methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-1H-indole;(1S,5S)-5-[5-(6-methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-1H-indole;(1R,5S)-6-(6-phenyl-pyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;(1R,5S)-6-(6-m-tolyl-pyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;(1R,5S)-3-methyl-6-(6-phenyl-pyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptane;(1R,5S)-5-[5-(3-methyl-3,6-diaza-bicyclo[3.2.0]hept-6-yl)-pyridin-2-yl]-1H-indole;(1S,5S)-5-[6-(3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-3-yl]-1H-indole;(1S,5S)-3-(5-phenyl-pyridin-2-yl)-3,6-diaza-bicyclo[3.2.0]heptane;(1S,5S)-6-methyl-3-(5-phenyl-pyridin-2-yl)-3,6-diaza-bicyclo[3.2.0]heptane;(1S,5S)-5-[6-(6-methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-3-yl]-1H-indole;or a pharmaceutically acceptable salt, ester, or amide thereof.
 10. Thecompound of claim 1 that is(1R,5R)-5-[5-(6-methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-1H-indoleor a pharmaceutically acceptable salt, ester, or amide thereof.
 11. Thecompound of claim 1 that is(1S,5S)-5-[5-(6-methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-2-yl]-1H-indoleor a pharmaceutically acceptable salt, ester, or amide thereof.
 12. Thecompound of claim 1 that is5-[5-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-2-yl]-1H-indoleor a pharmaceutically acceptable salt, ester, or amide thereof.
 13. Thecompound of claim 1 that is2-(6-thiophen-3-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole or apharmaceutically acceptable salt, ester, or amide thereof.
 14. Thecompound of claim 1 that is2-methyl-5-(6-thiophen-3-yl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrroleor a pharmaceutically acceptable salt, ester, or amide thereof.
 15. Thecompound of claim 1 that is(1R,5R)-6-Methyl-3-(6-phenyl-pyridin-3-yl)-3,6-diaza-bicyclo[3.2.0]heptaneor a pharmaceutically acceptable salt, ester, or amide thereof.
 16. Thecompound of claim 1 that is2-(6-phenyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole or apharmaceutically acceptable salt, ester, or amide thereof.
 17. Thecompound of claim 1 that is2-methyl-5-(6-phenyl-pyridin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole or apharmaceutically acceptable salt, ester, or amide thereof.
 18. Thecompound of claim 1 that is(1S,5S)-5-[6-(6-methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl)-pyridin-3-yl]-1H-indoleor a pharmaceutically acceptable salt, ester, or amide thereof.
 19. Thecompound of claim 1 that is2-(5-phenyl-pyridin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole or apharmaceutically acceptable salt, ester, or amide thereof.
 20. Apharmaceutical composition comprising a therapeutically effective amountof the compound of claim 1 or a pharmaceutically acceptable salt, ester,or amide thereof, in combination with a pharmaceutically acceptablecarrier.